New Drugs of 1999
Michael A. Mancano, PharmD
Dr. Mancano is an Associate Professor of Clinical Pharmacy at the Temple University School of Pharmacy in Philadelphia, PA.
During 1999 many unique and important medications were approved for use by the FDA. This continuing education program will review, in depth, 28 new drug approvals of 1999. New treatments were approved for Parkinson’s disease, breast cancer, obesity management, osteoarthritis, partial-onset seizures, and insomnia, to name a few.
The drug reviews contained in this article are comprised of the current dosing guidelines, common adverse effects, contraindications to therapy, and the current FDA-approved indication for each drug. This review is designed to focus on the new molecular entities that pharmacists will most likely come in contact with in their practice. Because of space constraints and the large number of new molecular entities approved during 1999, I have selected 28 new drugs for in-depth review for this continuing education program. The reader is directed to
Table 1 for a complete list of the new molecular entities approved by the FDA during 1999.
Table 2 contains a list of the new formulation approvals for 1999. The new formulation approvals are new dosage forms or new formulations of active ingredients already on the market.
Table 3 contains a list of new combination approvals for 1999. The new combination approvals are drugs that contain two or more compounds—the combination of which has not been marketed together in a product.
Table 4 contains the new derivative approvals. The new derivative approvals are a chemical derived from an active ingredient already marketed as a “parent drug.”
Alitretinoin Gel 0.1% (Panretin)
Ligand Pharmaceuticals Inc.
Alitretinoin is chemically related to vitamin A. Alitretinoin is a naturally occurring endogenous retinoid that binds to and activates all known intracellular retinoid receptor subtypes. Once activated, these receptors function as transcription factors that regulate the expression of genes which control the process of cellular differentiation and proliferation in both normal and neoplastic cells.
Alitretinoin is indicated for the topical treatment of cutaneous lesions in patients with AIDS-related Kaposi’s sarcoma. Alitretinoin gel is not indicated when systemic anti-Kaposi’s sarcoma therapy is required.
Alitretinoin gel should initially be applied twice a day to cutaneous Kaposi’s sarcoma lesions. The application frequency can be gradually increased to three or four times daily according to individual lesion tolerance. If application-site toxicity occurs, the application frequency can be reduced. Should severe irritation occur, application of the drug can be temporarily discontinued for a few days until the symptoms subside. Sufficient gel should be applied to cover the lesion with a generous coating. The gel should be allowed to dry for 3 to 5 minutes before covering with clothing. Application of the gel to normal skin surrounding the lesion should be avoided because of the potential for irritation. Occlusive dressings should not be utilized with alitretinoin gel.
The response to therapy may be seen as soon as 2 weeks after initiation of therapy, but most patients require longer application. With continued application, further benefit may be attained. Some patients have required more than 14 weeks to respond.
Retinoids, as a class, have been associated with photosensitivity. There were no reports of photosensitivity associated with the use of alitretinoin gel in clinical studies. Nonetheless, because in vitro data indicate alitretinoin may have a weak photosensitizing effect, patients should be advised to minimize exposure of treated areas to sunlight and sunlamps during the use of alitretinoin gel.
Alitretinoin is contraindicated in patients with a known hypersensitivity to retinoids or any of the product’s ingredients. Because of the potential for fetal harm from retinoids, women of childbearing potential should be advised to avoid becoming pregnant if they are to receive alitretinoin therapy.
Alitretinoin gel 0.1% is supplied in tubes containing 60 grams of gel.
Amprenavir is an inhibitor of the human immunodeficiency virus (HIV) protease. Amprenavir is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. This combination is based on analysis of plasma HIV RNA levels and CD4 cell counts in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating long-term suppression of HIV RNA or disease progression with amprenavir.
The recommended oral dosage of amprenavir capsules for adults is 1,200 mg (eight 150-mg capsules) twice daily in combination with other antiretroviral agents. The recommended dosage of amprenavir may be taken with or without food, however, a high-fat meal decreases the absorption of amprenavir and should be avoided. Adult and pediatric patients should be advised not to take supplemental vitamin E, since the vitamin E content of amprenavir capsules and oral solution exceeds the Reference Daily Intake (adults 30 IU, children approximately 10
IU).
For adolescents, ages 13 to 16 years, the recommended oral dose of amprenavir capsules is 1,200 mg (eight 150-mg capsules) twice daily in combination with other antiretroviral agents. For patients between 4 and 12 years of age or for patients 13 to 16 years of age who weigh less than 50 kg, the recommended oral dose of amprenavir capsules is 20 mg/kg twice daily or 15 mg/kg three times daily (maximum daily dose of 2,400 mg) in combination with other antiretroviral agents.
Amprenavir capsules and oral solution are not interchangeable on a milligram-per-milligram basis. The recommended oral dose of amprenavir oral solution for patients between 4 and 12 years of age or for patients 13 to 16 years of age who weigh less than 50 kg is 22.5 mg/kg (1.5 mL/kg) twice daily or 17 mg/kg (1.1 mL/kg) three times daily (to a maximum daily dose of 2,800 mg in combination with other antiretroviral agents).
Amprenavir should be used with caution in patients with moderate-to-severe hepatic impairment. Patients with a Child-Pugh score ranging from 5 to 8 should receive a reduced dose of amprenavir capsules of 450 mg twice daily, and patients with a Child-Pugh score ranging from 9 to 12 should receive a reduced dose of amprenavir capsules of 300 mg twice daily.
Amprenavir is an inhibitor of cytochrome CYP3A4 metabolism; therefore, it should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. The following drugs should not be coadministered with amprenavir: astemizole, rifampin, midazolam, triazolam, bepridil, dihydroergotamine, ergotamine, and cisapride. The following agents can be coadministered with amprenavir, however, concentration monitoring (or international normalized ratio [INR] monitoring for warfarin) is required for these agents: amiodarone, lidocaine (systemic), quinidine, warfarin, and tricyclic antidepressants. In patients receiving amprenavir and rifabutin, the rifabutin dose should be reduced to half of the recommended dose and a complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia in patients receiving amprenavir and rifabutin.
Other potentially significant drug interactions can be caused by CYP3A4 induction. Anticonvulsants such as phenobarbital, phenytoin, and carbamazepine may decrease amprenavir concentrations. Cholesterol-lowering agents such as atorvastatin, cerivastatin, lovastatin, and simvastatin may have their serum concentrations increased by amprenavir, which could increase their activity or toxicity. And, 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 ritonavir (a similar agent). Patients taking antacids (or didanosine) should take amprenavir at least 1 hour before or after antacid or didanosine use.
Amprenavir is a sulfonamide. The potential for cross-sensitivity between drugs in the
sulfonamide class and amprenavir is unknown. Patients with a known sulfonamide allergy should be treated with caution.
Patients should be informed that amprenavir is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of amprenavir are unknown at this time. Patients should be told there are currently no data demonstrating that therapy with amprenavir can reduce the risk of transmitting HIV to others through sexual contact.
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.
In clinical trials with amprenavir, adverse events experienced by patients receiving amprenavir were gastrointestinal in nature, such as nausea, vomiting, diarrhea, loose stools, and taste disorders. Patients have also experienced oral or perioral paresthesias and peripheral paresthesias. Severe or life-threatening rash, including Stevens-Johnson syndrome, has occurred in 1% of recipients of amprenavir while 4% of amprenavir recipients developed rash. Amprenavir therapy should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms.
Amprenavir is supplied as 50-mg capsules in bottles of 480 and as 150-mg capsules in bottles of 240. Amprenavir is also available as an oral solution containing 15 mg amprenavir per 1 mL of a grape-, bubble gum-, or peppermint-flavored liquid in bottles containing 240 mL of oral solution.
Bexarotene is a member of a subclass of retinoids that selectively activate retinoid X receptors. These retinoid receptors have biologic activity distinct from that of retinoid acid receptors.
Bexarotene is indicated for the treatment of cutaneous manifestations of T-cell lymphoma in patients who are refractory to at least one prior systemic therapy.
The recommended initial dose of bexarotene is 300 mg/m2 per day. Bexarotene capsules should be taken as a single oral daily dose with a meal. The initial starting dose of 300 mg/m2 per day can be adjusted to 200 mg/m2 per day then to 100 mg/m2 per day or temporarily suspended if necessitated by toxicity. When toxicity is controlled, doses may be carefully readjusted upward. If there is no tumor response after 8 weeks of treatment and if the initial dose of 300 mg/m2 per day is well tolerated, the dose may be escalated to 400 mg/m2 per day with careful monitoring. Therapy with bexarotene should continue as long as the patient is deriving benefit. Clinical experience shows that bexarotene has been administered for up to 97 weeks in clinical trials.
No specific studies to evaluate drug interactions with bexarotene have been conducted. Bexarotene’s oxidative metabolites appear to be formed by CYP3A4. Because bexarotene is metabolized by CYP3A4, ketoconazole, itraconazole, erythromycin, gemfibrozil, grapefruit juice, and other inhibitors of CYP3A4 would be expected to lead to an increase in
plasma bexarotene concentrations. Furthermore, rifampin, phenytoin, phenobarbital, and other inducers of CYP3A4 may cause a reduction in plasma bexarotene concentrations.
The most common adverse events reported with an incidence of at least 10% in patients receiving bexarotene at an initial dose of 300 mg/m2 per day are lipid abnormalities, elevated triglycerides, elevated total and low-density lipoprotein cholesterol, and decreased high-density lipoprotein cholesterol. Hypothyroidism, headache, asthenia, rash, leukopenia, anemia, nausea, infection, peripheral edema, abdominal pain, and dry skin have also been reported.
A small number of patients receiving bexarotene have experienced acute pancreatitis. These cases were associated with marked elevation in fasting serum triglycerides, the lowest being 770 mg/dL in one patient.
In addition, elevations in liver function tests have been observed in patients receiving bexarotene, with one patient death from cholestasis progressing to liver failure. Therefore, because of the extensive hepatic metabolism of bexarotene, hepatic impairment would be expected to lead to greatly reduced clearance. Bexarotene should be used only with great caution in this population.
Bexarotene is rated as a pregnancy category X medication and precautions to prevent pregnancy and birth defects in women of childbearing potential should be undertaken.
Bexarotene is supplied as 75-mg capsules in bottles of 100.
Cilostazol is a quinolinone derivative that inhibits cellular phosphodiesterase. Cilostazol is indicated for the reduction of symptoms of intermittent claudication as indicated by an increased walking distance.
The recommended dosage of cilostazol is 100 mg twice daily taken at least half an hour before or 2 hours after breakfast and dinner. The beneficial effects of cilostazol may not be immediate. Although the patient may experience benefit 2 to 4 weeks after initiation of therapy, treatment for up to 12 weeks may be required before beneficial effect is experienced.
Since cilostazol is extensively metabolized by cytochrome P-450 isoenzymes, caution should be exercised when cilostazol is coadministered with inhibitors of CYP3A4. A dose of 50 mg twice daily should be considered during coadministration of such inhibitors of CYP3A4 as ketoconazole, itraconazole, erythromycin, and diltiazem, and during coadministration of inhibitors of CYP2C19, such as omeprazole. CYP3A4 is also inhibited by grapefruit juice. Because the magnitude and timing of this interaction have not yet been investigated, patients receiving cilostazol should avoid consuming grapefruit juice.
Adverse events experienced with cilostazol therapy in clinical trials were headache, palpitation, diarrhea, tachycardia, dyspepsia, peripheral edema, dizziness, and rhinitis.
Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared with placebo in patients with class III-IV congestive heart failure. Cilostazol is contraindicated in patients with congestive heart failure of any severity.
Cilostazol is supplied as 50- and 100-mg tablets in bottles of 60.
Dalfopristin/quinupristin is a streptogramin antibacterial agent for intravenous administration. This formulation is a combination of two semisynthetic pristinamycin derivatives, quinupristin (derived from pristinamycin I) and dalfopristin (derived from pristinamycin IIA), in a ratio of 30:70.
Dalfopristin/quinupristin is indicated in adults for the treatment of
serious or life-threatening infection caused by susceptible strains of vancomycin-resistant Enterococcus faecium
(VREF).
Dalfopristin/quinupristin has been approved under the FDA’s accelerated approval regulations that allow marketing of products for use in life-threatening conditions when other therapies are not available. Approval of drugs for marketing under these regulations is based on a demonstrated effect on a surrogate end point—clearance of VREF from the bloodstream—that is likely to predict clinical benefit. A study to verify the clinical benefit of therapy with
dalfopristin/quinupristin on traditional clinical end points (such as cure of the underlying infection) is presently under way.
Dalfopristin/quinupristin is also indicated for the treatment of complicated skin and skin structure infections caused by
Staphylococcus aureus (methicillin
susceptible) or Streptococcus pyogenes.
Dalfopristin/quinupristin should be administered by intravenous infusion in 5% dextrose over a 60-minute period. If necessary, central venous access can be used to administer dalfopristin/quinupristin to decrease the incidence of venous irritation. The dose of dalfopristin/quinupristin in the treatment of VREF is 7.5 mg/kg, administered every 8 hours with a treatment duration that should be determined based on the site and severity of the infection. The dose of dalfopristin/quinupristin in the treatment of complicated skin and skin structure infections is 7.5 mg/kg, administered every 12 hours for 7 days. No dosage adjustment is necessary for elderly patients or patients with renal insufficiency; however, a dosage reduction is recommended in patients with hepatic insufficiency.
In vitro drug interaction studies have demonstrated that dalfopristin/quinupristin significantly inhibits the CYP3A4 metabolism of cyclosporine, midazolam, nifedipine, and terfenadine. Therapeutic drug monitoring of cyclosporine should be performed if patients are to undergo concomitant therapy with dalfopristin/quinupristin. It is reasonable to expect that the concomitant administration of dalfopristin/ quinupristin and other drugs primarily metabolized by the CYP3A4 enzyme system may likely result in increased plasma concentrations of these drugs, which could increase or prolong their therapeutic effect and/or increase adverse reactions. Therefore, the coadministration of dalfopristin/quinupristin with CYP3A4 substrates with a narrow therapeutic window requires caution and monitoring of these drugs whenever possible. Before utilizing dalfopristin/quinupristin in a patient, it would be prudent to evaluate their therapeutic regimen for CYP3A4 substrates.
Adverse effects with the administration of dalfopristin/quinupristin are primarily infusion-related. Patients have reported inflammation, edema, and pain at the infusion site, thrombophlebitis, headache, pruritus, and rash.
Dalfopristin/quinupristin is supplied as single-dose, 10-mL vials containing dalfopristin/quinupristin 500 mg (150 mg of quinupristin and 350 mg dalfopristin) in trays containing 10 vials.
Denileukin diftitox is a recombinant DNA-derived cytotoxic protein composed of the amino acid sequences of diphtheria toxin fragments A and B-H and is followed by the sequences for interleukin-2 (IL-2). Studies suggest that denileukin diftitox interacts with the high-affinity IL-2 receptor on the cell surface and inhibits cellular protein synthesis, resulting in cell death within hours. Denileukin diftitox is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor. The safety and efficacy of denileukin diftitox in patients with CTCL whose malignant cells do not express the CD25 component of the IL-2 receptor have not been examined.
The recommended treatment regimen for denileukin diftitox (one treatment cycle) is 9 or 18 mcg/kg per day, administered intravenously for 5 consecutive days every 21 days. Denileukin diftitox is for intravenous administration only and should be infused over at least 15 minutes. If infusion-related adverse reactions occur, the infusion should be discontinued or the rate should be reduced, depending on the severity of the reaction. The optimal duration of therapy has not been determined; however, only 2% of patients who did not demonstrate at least a 25% decrease in tumor burden prior to the fourth course of treatment subsequently responded.
All patients in clinical trials with denileukin diftitox experienced one or more adverse events. Twenty-one percent of patients required hospitalization for drug-related adverse events; the most common reasons were evaluation of fever, management of vascular leak syndrome, or dehydration secondary to gastrointestinal toxicity. Five percent of clinical adverse reactions were severe or life-threatening. The occurrence of adverse events tended to diminish in frequency after the first two courses, which is possibly related to antibody development.
As mentioned earlier, there are two distinct clinical syndromes associated with denileukin diftitox infusion—an acute hypersensitivity-type symptom complex and a flulike symptom complex. Overall, 69% of patients had infusion-related, hypersensitivity-type symptoms. Approximately half of the events occurred on the first day of dosing regardless of the treatment cycle. The symptoms of this acute hypersensitivity symptom complex are hypotension, back pain, dyspnea, vasodilation, rash, chest pain or tightness, and tachycardia.
Patients receiving denileukin diftitox may also experience a flu-like syndrome within several hours to days after denileukin diftitox infusion. The symptoms are one or more of the following: fever and/or chills, asthenia, myalgias, and arthralgias. In the majority of patients, these symptoms were mild to moderate and responded to treatment with antipyretics and/or antiemetics. Antipyretics and/or antiemetics were used to relieve flulike symptoms; however, the usefulness of these agents in ameliorating these toxicities or as prophylactic agents to decrease the incidence of the acute, flulike toxicities has not been prospectively studied.
Denileukin diftitox is contraindicated for use in patients with a known hypersensitivity to denileukin diftitox or any of its components: diphtheria toxin, IL-2, or excipients. Patients should be monitored carefully for infection, since patients with CTCL have a predisposition to cutaneous infection. Also, the binding of denileukin diftitox to activated lymphocytes and macrophages can lead to cell death and may impair immune function in patients.
Denileukin diftitox is supplied as a 150-mcg/mL, sterile, frozen solution (300 mcg in 2 mL) in a sterile, single-use vial. Denileukin diftitox is supplied as six vials in a package and is recommended to be stored frozen at or below –10oC.
Dexmedetomidine is a relatively selective alpha-2 adrenoreceptor agonist with sedative properties. It is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Dexmedetomidine should be administered by continuous infusion not to exceed 24 hours.
Dexmedetomidine should be administered using a controlled infusion device. Dexmedetomidine dosing should be individualized and titrated to the desired clinical effect. For adult patients, dexmedetomidine is generally initiated with a loading infusion of 1 mcg/kg over 10 minutes followed by a maintenance infusion of 0.2 to 0.7 mcg/kg per hour. The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation. Dosage reductions may need to be
considered for patients with renal impairment and hepatic impairment. Dexmedetomidine must be diluted in 0.9% sodium chloride solution prior to administration, with preparation being the same for the loading dose or maintenance infusion.
Overall, the most frequently observed treatment-emergent adverse events include hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia, and anemia. Reports of hypotension and bradycardia have been associated with dexmedetomidine infusion. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine, increasing the rate of concomitant intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine. Some patients receiving dexmedetomidine have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms. Although not specifically studied, if dexmedetomidine is administered chronically and stopped abruptly, withdrawal symptoms similar to those reported for another alpha-2 adrenergic agent, clonidine, may result. These symptoms include nervousness, agitation, and headaches accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma.
Dexmedetomidine is supplied as a 100-mcg/mL solution in 2-mL glass vials or 2-mL glass ampules.
Dofetilide is an oral antiarrhythmic drug with Vaughan Williams Class III antiarrhythmic activity. To minimize the risk of induced arrhythmia, patients initiated or reinitiated on dofetilide should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiogram (ECG) monitoring, and cardiac resuscitation. Dofetilide is available only to hospitals and prescribers who have received appropriate dofetilide dosing and treatment initiation education.
Dofetilide is indicated for the conversion of atrial fibrillation or flutter to normal sinus rhythm; however, dofetilide has not been shown to be effective in patients with paroxysmal atrial fibrillation. Dofetilide is also indicated for the maintenance of normal sinus rhythm (delay in the time to recurrence of atrial fibrillation/atrial flutter) in patients with atrial fibrillation or flutter of greater than 1 week in duration who have been converted to normal sinus rhythm. Because dofetilide can cause life-threatening ventricular arrhythmias, it should be reserved for patients in whom atrial fibrillation or flutter is highly symptomatic.
Calculation of creatinine clearance for all patients must precede administration of the first dose of dofetilide. Initial dosing of dofetilide is also based on baseline ECG parameters for each patient. If the patient’s creatinine clearance is greater than 60 mL/min, then dofetilide can be initiated at 500 mcg twice daily. Creatinine clearance of 40 to less than 60 mL/min requires dosing of 250 mcg twice daily, and creatinine clearance of 20 to less than 40 mL/min requires dosing of 125 mcg twice daily. Patients with a calculated creatinine clearance of less than 20 mL/min should not receive dofetilide therapy. The calculation of the patient’s creatinine clearance is essential in correctly dosing dofetilide, because the clearance of dofetilide decreases with decreasing creatinine clearance. In addition, the increase in QT interval and the risk of ventricular arrhythmias are directly related to plasma concentrations of dofetilide; dosage adjustment based on creatinine clearance is critically important. After the initial dosing of dofetilide, the patient’s dosage must be titrated based on continuous ECG monitoring.
Patients to be discharged on dofetilide therapy from an in-patient setting must have an adequate supply of dofetilide at the patient’s individualized dosage to allow uninterrupted dosing until the patient receives their first outpatient supply. Inpatient and subsequent outpatient discharge and refill prescriptions are filled only upon confirmation that the prescribing physician has received applicable dosing and treatment education programs. For this purpose, a list of hospitals and physicians who have completed one of the education programs is maintained for use by pharmacists (contact Pfizer Pharmaceuticals for more details concerning the list).
The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), or ketoconazole with dofetilide is contraindicated, since each of the drugs cause a substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation transport system, such as prochlorperazine and megestrol, should not be used in patients receiving dofetilide. Prior to initiation of dofetilide, assessment of a patient’s medication history should include all over-the-counter, prescription, and herbal/natural preparations, with emphasis on preparations that may affect the pharmacokinetics of dofetilide, such as mentioned above.
The most frequent reason for discontinuation of dofetilide therapy is induction of ventricular tachycardia, with the most frequently experienced adverse effects being headache, chest pain, and dizziness.
Dofetilide is supplied as 125-, 250-, and 500-mcg capsules in bottles of 14 and 60 capsules.
Doxercalciferol is a synthetic vitamin D analog that undergoes metabolic activation in vivo to form 1-alpha, 25-dihydroxyvitamin D2 (1-alpha, 25-[OH]2D2), a naturally occurring, biologically active form of vitamin D2. Calcitriol (1-alpha, 25-[OH]2 D3) and 1-alpha, 25-(OH)2D2 regulate blood calcium at levels required for essential body functions. Specifically, the biologically active vitamin D metabolites control the intestinal absorption of dietary calcium, the tubular reabsorption of calcium by the kidneys and, in conjunction with parathyroid hormone (PTH), the mobilization of calcium from the skeleton.
Doxercalciferol is indicated for the reduction of elevated PTH levels in the management of secondary hyperparathyroidism in patients undergoing chronic renal dialysis. The optimal dose of doxercalciferol must be carefully determined for each patient. The recommended initial dose of doxercalciferol is 10 mcg administered three times weekly at dialysis (approximately every other day). The initial dose should be adjusted, as needed, to lower blood PTH into the range of 150 to 300 pg/mL. The dose may be increased at 8-week intervals by 2.5 mcg if PTH is not lowered by 50% and fails to reach the target range. The maximum recommended dose of doxercalciferol is 20 mcg administered three times a week at dialysis for a total of 60 mcg/week. Drug administration should be suspended if PTH falls below 100 pg/mL and restarted 1 week later at a dose at least 2.5 mcg lower than the last administered dose. During titration, PTH, serum calcium, and serum phosphorus levels should be obtained weekly. If hypercalcemia, hyperphosphatemia, or a serum calcium times serum phosphorus product greater than 70 is noted, the drug should be immediately suspended until these parameters are appropriately lowered. Then, the drug should be restarted at a dose at least 2.5 mcg lower.
During treatment with doxercalciferol, patients usually require dose titration, as well as adjustment in cotherapy (ie, dietary phosphate binders) to effect and sustain PTH suppression while maintaining serum calcium and phosphorus within prescribed ranges.
The principal adverse effects of treatment with doxercalciferol are hypercalcemia, hyperphosphatemia, and oversuppression of PTH. Prolonged hypercalcemia can lead to calcification of soft tissues, including the heart and arteries, and hyperphosphatemia can exacerbate hyperparathyroidism. Oversuppression of PTH may lead to adynamic bone syndrome. All of these potential adverse effects should be managed by regular patient monitoring and appropriate dosage adjustments.
Doxercalciferol is available as 2.5-mcg soft gelatin capsules in bottles of 50 capsules.
Entacapone is an inhibitor of catechol-O-methyltransferase (COMT) used in the treatment of Parkinson’s disease as an adjunct to levodopa/carbidopa therapy. Entacapone is indicated as an adjunct to levodopa/carbidopa to treat patients with idiopathic Parkinson’s disease who experience the signs and symptoms of end-of-dose “wearing off.” Entacapone’s effectiveness has not been systematically evaluated in patients with idiopathic Parkinson’s disease who do not
experience end-of-dose wearing off.
The recommended dose of entacapone is one 200-mg tablet administered concomitantly with each carbidopa/levodopa dose to a maximum of eight times daily, 1,600 mg/day. Clinical experience with daily doses above 1,600 mg is limited. Entacapone should always be administered in association with carbidopa/levodopa, since entacapone has no antiparkinsonian effect of its own. In clinical trials, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been greater than or equal to 800 mg, or if the patients had moderate or severe dyskinesias before beginning treatment.
Rapid withdrawal or abrupt reduction in the entacapone dose could lead to emergence of signs and symptoms of Parkinson’s disease and may lead to hyperpyrexia and confusion, a symptom complex resembling neuroleptic malignant syndrome.
Monoamine oxidase (MAO) and COMT are two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of entacapone and a non-selective MAO inhibitor would result in the inhibition of the majority of the pathways responsible for normal catecholamine metabolism. For this reason, patients should ordinarily not be treated concomitantly with entacapone and a nonselective MAO inhibitor. Entacapone can be taken concomitantly with a selective MAO-B inhibitor such as selegiline.
Patients should be informed that hallucinations can occur with the use of entacapone. In addition, postural hypotension may occur with or without symptoms such as dizziness, nausea, syncope, and sweating. Hypotension may occur more frequently during initial therapy. Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and at the initiation of treatment with entacapone.
Patients should be advised not to drive or operate other complex machinery until they have gained sufficient experience with entacapone to gauge whether it affects their mental and/or motor performance adversely. Because of the possible sedative effects, caution should be used when patients are taking other central nervous system (CNS) depressants in combination with entacapone. Patients should also be advised of the possibility of nausea and an increase in dyskinesia with the use of entacapone.
Entacapone may cause a change in color of the patient’s urine, a brownish-orange discoloration, that is not clinically relevant. In clinical trials with entacapone, 10% of patients reported urine discoloration.
Entacapone is supplied as 200-mg tablets in bottles of 10, 100, and 500 tablets.
Epirubicin is an anthracycline cytotoxic agent intended for intravenous
administration. Epirubicin is the 4´-epimer of doxorubicin and is a semisynthetic derivative of daunorubicin. Epirubicin is indicated as a
component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer.
Epirubicin is administered to patients by intravenous infusion.
Epirubicin is given in repeated 3- to 4-week cycles. The total dose of epirubicin may be given on day 1 of each cycle or divided equally and given on days 1 and 8 of each cycle. The recommended starting dose of epirubicin is 100 to 120 mg/m2. The selected starting dose is based on concomitant chemotherapeutic agents that are chosen. Dose modifications after the first treatment cycle should be made based on hematologic and nonhematologic toxicities.
Patients should be informed of the expected adverse effects of epirubicin, including gastrointestinal symptoms (nausea, vomiting, diarrhea, and stomatitis) and potential neutropenic complications. Patients should consult their physician if vomiting, dehydration, fever, evidence of infection, symptoms of congestive heart failure, or injection-site pain occurs following therapy with epirubicin. Patients should be informed that they will almost certainly develop alopecia. Patients should be advised that their urine may appear red for 1 to 2 days after administration of epirubicin and that they should not be alarmed. Patients should understand that there is a risk of irreversible myocardial damage associated with treatment with epirubicin, as well as a risk of treatment-related leukemia. Because epirubicin may induce chromosomal damage in sperm, men undergoing treatment with epirubicin should use effective contraceptive methods. Women treated with epirubicin may develop irreversible amenorrhea or premature menopause.
Treatment with cimetidine should be stopped if a patient is to receive epirubicin, because cimetidine can increase levels of epirubicin.
Patients should not be treated with epirubicin injection if they have any of the following conditions: baseline neutrophil count less than 1,500 cells/mm3; severe myocardial insufficiency; previous treatment with anthracyclines up to the maximum cumulative dose; hypersensitivity to epirubicin, other anthracyclines or anthracenediones; or severe hepatic dysfunction.
Epirubicin is supplied in single-use vials containing 2 mg/1 mL of epirubicin in 25- and 100-mL vials.
Exemestane is an irreversible, steroidal aromatase inactivator. It is indicated for the treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.
The recommended dose of exemestane is 25 mg once daily following a meal. Treatment with exemestane should continue until tumor progression is evident. The safety of chronic dosing in patients with moderate or severe hepatic or renal impairment has not been studied. Based on experience with exemestane at repeated doses up to 200 mg daily, patients demonstrated a moderate increase in non–life-threatening adverse events, therefore, dosage adjustment does not appear to be necessary.
Exemestane is extensively metabolized by CYP3A4, but coadministration of ketoconazole, a potent inhibitor of CYP3A4, has no significant effect on exemestane pharmacokinetics. Significant pharmacokinetic interactions mediated by inhibition of CYP isoenzymes appear unlikely; however, a possible decrease of exemestane plasma levels by known inducers of CYP3A4 cannot be excluded. Exemestane should not be administered to premenopausal women. Exemestane should not be coadministered with estrogen-containing agents, because they could interfere with its pharmacologic action.
Exemestane is generally well tolerated, and adverse events are usually mild to moderate. Adverse events related to exemestane use are hot flashes, nausea, fatigue, increased sweating, and increased appetite.
Exemestane is supplied as 25-mg tablets in bottles of 30 tablets.
Ferric sodium gluconate is an injectable iron replacement product. Ferric sodium gluconate is indicated for the treatment of iron deficiency anemia in patients undergoing chronic hemodialysis who are receiving supplemental erythropoietin therapy.
The dosage of ferric sodium gluconate is expressed in terms of elemental iron. Each 5-mL ampule contains 62.5 mg of elemental iron (12.5 mg/mL). Before initiating therapy, an intravenous test dose of 2 mL of ferric sodium gluconate injection is recommended. The test dose should be diluted in 50 mL of 0.9% sodium chloride solution and administered over 60 minutes. The recommended dosage of ferric sodium gluconate for the repletion treatment of iron deficiency in hemodialysis patients is 10 mL of ferric sodium gluconate (125 mg of elemental iron) diluted in 100 mL of 0.9% sodium chloride solution administered intravenously over 1 hour. Most patients will require a minimum cumulative dose of 1 gram of elemental iron, administered over eight sessions at sequential dialysis treatments to achieve favorable hemoglobin or hematocrit response.
It is important to note that, in general, iron is not easily eliminated from the body and accumulation can be toxic. Unnecessary therapy with parenteral iron will cause excess storage of iron with the consequent possibility of iatrogenic hemosiderosis.
Potentially fatal hypersensitivity reactions characterized by cardiovascular collapse, cardiac arrest, bronchospasm, oral or pharyngeal edema, angioedema, urticaria, or pruritus sometimes associated with pain and muscle spasm of the chest or back have been reported rarely in patients receiving ferric sodium gluconate. Additionally, hypotension associated with flushing, lightheadedness, malaise, fatigue, weakness, and severe pain in the chest, back, flanks, or groin has been associated with rapid administration of intravenous iron. These hypotensive reactions are not associated with signs of hypersensitivity and have usually resolved within 1 to 2 hours.
Ferric sodium gluconate is supplied as 5-mL ampules containing 62.5 mg of elemental iron for intravenous use, packaged in cartons of 10 ampules.
Gatifloxacin is a synthetic broad-spectrum quinolone antibacterial agent for oral or intravenous administration. Gatifloxacin is indicated for the treatment of adults age 18 and older with the following types of infections: acute bacterial exacerbation of chronic bronchitis, acute bacterial sinusitis, community- acquired pneumonia, uncomplicated urinary tract infections, complicated urinary tract infections, pyelonephritis, uncomplicated urethral and cervical gonorrhea, or acute uncomplicated rectal infections in women.
Gatifloxacin can be utilized in patients presenting with susceptible strains of microorganisms in the previously outlined infection types.
The recommended dose for the treatment of community-acquired pneumonia is 400 mg of gatifloxacin once every 24 hours for 7 to 14 days. The recommended dose for the treatment of acute bacterial exacerbation of chronic bronchitis, complicated urinary tract infections, and pyelonephritis is 400 mg of gatifloxacin once every 24 hours for 7 to 10 days. The recommended dose of gatifloxacin for the treatment of acute sinusitis is 400 mg once every 24 hours for 10 days. Uncomplicated urethral gonorrhea in men and endocervical and rectal gonorrhea in women can be treated with gatifloxacin 400 mg as a single dose. Uncomplicated urinary tract infections can be treated with gatifloxacin 400 mg as a single dose or 200 mg once daily every 24 hours for 3 days.
Since gatifloxacin is primarily eliminated renally, a dosage modification of gatifloxacin is recommended for patients with a creatinine clearance of less than 40 mL/min, including patients on hemodialysis and those receiving continuous ambulatory peritoneal dialysis (CAPD). When the patient’s creatinine clearance is less than 40 mL/min, receiving hemodialysis or CAPD, the recommended dose of gatifloxacin is 400 mg as an initial dose followed by 200 mg daily. Single 400-mg doses of gatifloxacin for uncomplicated urinary tract infections and gonorrhea and 200-mg doses once daily for 3 days for the treatment of uncomplicated urinary tract infections require no dosage adjustment in patients with impaired renal function.
Antacids, sucralfate, metal cations, and multivitamins form chelates with quinolone antibiotics. Administration of gatifloxacin with antacids containing aluminum, magnesium or calcium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations, such as didanosine (Videx) chewable/ buffered tablets or the pediatric powder for oral solution, may substantially interfere with the absorption of gatifloxacin, resulting in systemic concentrations considerably lower than desired. Therefore, gatifloxacin should be taken at least 4 hours before or 8 hours after these drugs. Gatifloxacin can be administered without regard to food, including milk and dietary supplements containing calcium.
The potential for clinically significant pharmacokinetic drug interactions between gatifloxacin and theophylline, warfarin, digoxin, midazolam, cimetidine, and glyburide has been evaluated. There was no clinically significant effect of gatifloxacin on theophylline, warfarin, midazolam, digoxin, or glyburide kinetics. Theophylline, digoxin, and cimetidine did not affect the pharmacokinetics of gatifloxacin.
Gatifloxacin has been shown to prolong the QT interval of the ECG in some patients. The drug should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving class IA (quinidine, procainamide) or class III (amiodarone, sotalol) antiarrhythmic agents, because of a lack of clinical experience with the drug in these patient populations. Gatifloxacin may add to the QTc-prolonging effects of other drugs, such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants.
Quinolones may cause CNS adverse events, including nervousness, agitation, insomnia, anxiety, nightmares, or paranoia. Additional adverse reactions possible with gatifloxacin therapy are nausea, vaginitis, diarrhea, dizziness, and headache.
Gatifloxacin is supplied as 200-and 400-mg tablets in bottles of 30 tablets. Gatifloxacin is also supplied as single-use vials for intravenous administration containing 10 mg/mL in 20- (200 mg) and 40-mL (400 mg) vials.
Ketotifen is a relatively selective, noncompetitive histamine antagonist (H-1 receptor) and mast cell stabilizer. Ketotifen inhibits the release of mediators from cells involved in hypersensitivity reactions. Ketotifen is indicated for the temporary prevention of itching of the eye caused by allergic conjunctivitis.
The recommended dose of ketotifen fumarate ophthalmic solution is 1 drop in the affected eye(s) every 8 to 12 hours. Patients should be advised not to wear a contact lens if their eye is red. Ketotifen should not be used to treat contact lens–related irritation. The preservative in ketotifen, benzalkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red should be instructed to wait at least 10 minutes after instilling ketotifen before inserting their contact lenses.
In controlled clinical studies, conjunctival infection, headaches, and rhinitis were reported at an incidence of 10% to 25%. The occurrence of these side effects was generally mild. Some of these events were similar to the underlying condition being studied. Other ocular adverse reactions occurring less often are allergic reactions, burning or stinging, conjunctivitis, discharge, dry eyes, and eye pain.
Ketotifen fumarate ophthalmic solution is supplied as 5 mL of solution in 7.5-mL bottles with controlled dropper tips.
Levetiracetam is an antiepileptic drug whose precise mechanism of action is not known. Its antiepileptic effect does not appear to derive from any interaction with known mechanisms involved in inhibitory and excitatory neurotransmission.
Levetiracetam is indicated as adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy. Treatment with levetiracetam should be initiated with a daily dose of 1,000 mg/day, given as 500 mg twice daily. Additional dosing increments may be given: 1,000 mg/day additional every 2 weeks to a maximum recommended daily dose of 3,000 mg. Long-term experience at doses greater than 3,000 mg/day is relatively minimal, and there is no evidence that doses greater than 3,000 mg/day confer additional benefit. The dosage of levetiracetam needs to be adjusted downward if the patient manifests impaired renal function. Levetiracetam should be withdrawn gradually to minimize the potential of increased seizure frequency.
Patients should be instructed to notify their physician if they become pregnant or intend to become pregnant during therapy with levetiracetam since it is rated pregnancy category C. Patients should also be advised that levetiracetam may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery or engage in other hazardous activities until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their performance of those activities.
Levetiracetam is supplied as 250-, 500-, and 750-mg tablets in bottles of 100 and 500 tablets.
Moxifloxacin is a synthetic broad-spectrum antibacterial agent of the fluoroquinolone class. Moxifloxacin is indicated for the treatment of adults, aged 18 and over, with the following types of infections: acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and community- acquired pneumonia. Moxifloxacin can be utilized in patients presenting with susceptible strains of microorganisms in the previously outlined infection types.
The recommended dose of moxifloxacin for the treatment of acute bacterial sinusitis and community acquired pneumonia is 400 mg taken orally every 24 hours for 10 days. The recommended dose for the treatment of an acute bacterial exacerbation of chronic bronchitis is 400 mg taken orally every 24 hours for 5 days. No dosage adjustment is required for renally impaired patients or patients with mild hepatic insufficiency. However, because of the lack of clinical data available for moxifloxacin use in patients with moderate and severe hepatic insufficiency, moxifloxacin is not recommended in patients with moderate and severe hepatic insufficiency.
Antacids, sucralfate, metal cations, and multivitamins form chelates with quinolone antibiotics. Administration of moxifloxacin with antacids containing aluminum, magnesium, or calcium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations, such as didanosine (Videx) chewable/ buffered tablets or the pediatric powder for oral solution, may substantially interfere with the absorption of moxifloxacin, resulting in systemic concentrations considerably lower than desired. Therefore, moxifloxacin should be taken at least 4 hours before or 8 hours after these drugs.
The potential for pharmacokinetic drug interactions between moxifloxacin and theophylline, warfarin, digoxin, probenecid, ranitidine, and glyburide have been evaluated. There was no clinically significant effect of moxifloxacin on theophylline, warfarin, digoxin, or glyburide kinetics. Theophylline, digoxin, probenecid, and ranitidine did not affect the pharmacokinetics of moxifloxacin.
Moxifloxacin has been shown to prolong the QT interval of the ECG in some patients. The drug should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalemia, and patients receiving class IA (quinidine, procainamide) or class III (amiodarone, sotalol) antiarrhythmic agents, because of the lack of clinical experience with the drug in these patient populations. Moxifloxacin may add to the QTc-prolonging effects of other drugs, such as cisapride, erythromycin, antipsychotics, and tricyclic antidepressants.
Quinolones may cause CNS adverse events, including nervousness, agitation, insomnia, anxiety, nightmares, or paranoia. Additional adverse reactions possible with moxifloxacin therapy are nausea, diarrhea, dizziness, headache, abdominal pain, vomiting, taste perversion, abnormal liver function
tests, and dyspepsia.
Moxifloxacin is supplied as 400-mg tablets in bottles containing 30 tablets, and in ABC packs containing 5 tablets.
Orlistat is a lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats. Orlistat is indicated for obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. Orlistat is also indicated to reduce the risk for weight regain after prior weight loss. Orlistat is indicated for obese patients with an initial body mass index ˇ 30 kg/m2 or ˇ 27 kg/m2 in the presence of other risk factors, such as hypertension, diabetes, or dyslipidemia.
Orlistat is a reversible inhibitor of lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. Because undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control. Systemic absorption of the drug is therefore not needed for activity.
The recommended dose of orlistat is one 120-mg capsule three times daily with each main meal containing fat, during or up to 1 hour after the meal. Doses above 120 mg three times a day have not been shown to provide additional benefit. The patient should eat a nutritionally balanced, reduced-calorie diet that contains approximately 30% of calories from fat. The daily intake of fat, carbohydrate, and protein should be distributed over three main meals. If a meal is occasionally missed or contains no fat, the dose of orlistat can be omitted. Because orlistat has been shown to reduce the absorption of some fat-soluble vitamins and beta carotene, patients should be counseled to take a multivitamin containing fat-soluble vitamins to ensure adequate nutrition. The supplement should be taken at least 2 hours before or after administration of orlistat, such as at bedtime.
Based on fecal fat measurements, the effect of orlistat is seen as soon as 24 to 48 hours after dosing. At the recommended therapeutic dose of 120 mg three times daily, orlistat inhibits dietary fat absorption by approximately 30%. Upon discontinuation of therapy, fecal fat content usually returns to pretreatment levels within 48 to 72 hours.
Adverse reactions occurring during therapy with orlistat are generally mild and transient. Gastrointestinal symptoms are the most commonly observed treatment-associated adverse effects and are primarily attributed to orlistat’s mechanism of action. Commonly observed adverse events are oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation, and fecal incontinence. In general, the first occurrence of these events was within 3 months of starting therapy. Overall, approximately 50% of all episodes of gastrointestinal adverse events associated with orlistat treatment lasted less than 1 week, and a majority lasted no more than 4 weeks. However, gastrointestinal adverse events may occur in some individuals over a period of 6 months or longer.
Patients should be advised to adhere to dietary guidelines because gastrointestinal events may increase when orlistat is taken with a diet high in fat (greater than 30% of calories from fat). Some patients may develop increased levels of urinary oxalate following treatment with orlistat. Caution should be exercised in patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis.
Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis, and in patients with known hypersensitivity to orlistat. Organic causes of obesity, such as hypothyroidism, should be excluded before prescribing orlistat.
Orlistat is supplied as 120-mg capsules in bottles containing 90 capsules.
Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is via inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release.
Oseltamivir is indicated for the treatment of uncomplicated acute illness because of influenza infection in adults who have been symptomatic for no more than 2 days. The efficacy of oseltamivir in patients who begin treatment after 40 hours of symptoms has not been established. This indication is based on studies of naturally occurring influenza in which the predominant infection was with influenza A, and influenza challenge studies in which antiviral activity of oseltamivir was supported for influenza A and B.
The standard dosing for oseltamivir is 75 mg orally twice daily for 5 days. Treatment should begin within 2 days of onset of symptoms of influenza. Oseltamivir may be taken with or without food. However, when taken with food, tolerability may be enhanced in some patients. No dosage adjustment is necessary for patients with creatinine clearance above 30 mL/min. In patients with a creatinine clearance of less than 30 mL/min, it is recommended that the dose be reduced to 75 mg of oseltamivir once daily for 5 days. The drug has not been studied in patients with renal failure (creatinine clearance below 10 mL/min); therefore, caution is advised when administering the drug to those patient populations.
Patients should be instructed to take any missed doses as soon as they remember, except if it is within 2 hours of the next scheduled dose, and then continue to take oseltamivir at the usual times. Patients should also be informed that oseltamivir is not a substitute for a flu shot. Patients should continue receiving an annual flu shot according to guidelines on immunization practices. The most frequently reported adverse events in studies have been nausea and vomiting. Additional adverse events that may be encountered include bronchitis, insomnia, and vertigo.
Oseltamivir is supplied as 75-mg capsules in blister packs of 10 capsules.
Pemirolast is a mast cell stabilizer that inhibits the antigen-induced release of inflammatory mediators, such as histamine, leukotriene C4, D4, and E4 from human mast cells. In addition, pemirolast inhibits the chemotaxis of eosinophils into ocular tissue and blocks the release of mediators from human eosinophils.
Pemirolast potassium ophthalmic solution is indicated for the prevention of itching of the eye caused by allergic conjunctivitis. Symptomatic response to therapy, decreased itching, may be evident within a few days, but frequently requires treatment of up to 4 weeks.
Patients should be advised not to wear a contact lens if their eye is red. Pemirolast should not be used to treat contact lens–related irritation. The preservative in pemirolast, benzalkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red should be instructed to wait at least 10 minutes after instilling pemirolast before inserting their contact lenses.
The recommended dosage of pemirolast potassium is 1 to 2 drops in each affected eye four times daily.
The following ocular and non-ocular adverse reactions have been reported in patients receiving pemirolast potassium ophthalmic solution: headache, rhinitis, cold/flu symptoms, ocular burning, dry eye, foreign body sensation, and ocular discomfort.
Pemirolast potassium ophthalmic solution 0.1% is supplied in 10-mL dropper bottles.
Pioglitazone is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. Pharmacologic studies indicate that pioglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Pioglitazone improves glycemic control while reducing circulating insulin levels. Pioglitazone is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. Pioglitazone should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non–insulin-dependent diabetes mellitus). Pioglitazone is indicated for monotherapy. Pioglitazone is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.
Pioglitazone monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 or 30 mg once daily. For patients who respond inadequately to the initial dose of pioglitazone, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered.
Pioglitazone in combination with a sulfonylurea may be initiated at 15 or 30 mg once daily. The current sulfonylurea dose can be continued upon initiation of pioglitazone therapy. If patients report hypoglycemia, the dose of the sulfonylurea should be decreased.
Pioglitazone in combination with metformin may be initiated at 15 or 30 mg once daily. The current metformin dose can be continued upon initiation of pioglitazone therapy. It is unlikely that the dose of metformin will require adjustment because of hypoglycemia during combination therapy with pioglitazone.
Pioglitazone in combination with insulin may be initiated at 15 to 30 mg once daily. The current insulin dose can be continued upon initiation of pioglitazone therapy. In patients receiving pioglitazone and insulin, the insulin dose can be decreased by 10% to 25% if the patient reports hypoglycemia or if plasma glucose concentrations decrease to less than 100 mg/dL. Further adjustments should be individualized based on glucose-lowering response. Pioglitazone should be taken once daily without regard to meals.
The dose of pioglitazone should not exceed 45 mg once daily, since doses higher than 45 mg once daily have not been studied in placebo-controlled clinical studies. No placebo-controlled studies of more than 30 mg once daily have been conducted in combination therapy.
Dose adjustment in patients with renal insufficiency is not recommended. Therapy with pioglitazone should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (alanine aminotransferase [ALT] greater than 2.5 times the upper limit of normal) at the start of therapy. Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with pioglitazone and periodically thereafter. Liver function tests should be performed every 2 months for the first year and periodically thereafter. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine.
In premenopausal anovulatory patients with insulin resistance, treatment with thiazolidinediones, including pioglitazone, may result in resumption of ovulation. As a consequence of their improved insulin sensitivity, these patients may be at risk for pregnancy if adequate contraception is not used. Administration of another thiazolidinedione with an oral contraceptive containing ethinyl estradiol and norethindrone reduced plasma concentrations of both hormones by approximately 30%, which could result in loss of contraception. The pharmacokinetics of coadministration of pioglitazone and oral contraceptives have not been evaluated in patients receiving pioglitazone and an oral contraceptive.
Therefore, additional caution regarding contraception should be exercised in patients receiving pioglitazone and an oral contraceptive.
The cytochrome P-450 isoform CYP3A4 is partially responsible for the metabolism of pioglitazone. Specific formal pharmacokinetic interaction studies have not been conducted with pioglitazone and other drugs metabolized by this enzyme, such as erythromycin, astemizole, calcium channel blockers, cisapride, corticosteroids, HMG-CoA reductase inhibitors, tacrolimus, triazolam, and trimetrexate, as well as inhibitory drugs such as ketoconazole and
itraconazole.
Adverse events reported in clinical trials with pioglitazone were upper respiratory infection, headache, sinusitis, myalgia, and pharyngitis.
Pioglitazone is supplied as 15-, 30-, and 45-mg tablets in bottles of 30, 90, and 500 tablets.
Rabeprazole is a proton-pump inhibitor that suppresses gastric acid secretion by inhibiting gastric H+, K+ ATPase at the secretory surface of the gastric parietal cell. Rabeprazole is indicated for the short-term treatment, up to 4 weeks, in the healing and symptomatic relief of duodenal ulcers and for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome. In addition, rabeprazole is indicated for short-term treatment, 4 to 8 weeks, in the healing of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of therapy, an additional 8-week course of rabeprazole may be considered. Rabeprazole is also indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative GERD.
The recommended dose of rabeprazole is 20 mg once daily for all indications except for the treatment of pathological hypersecretory conditions in which dosing must be individualized for the patient. The recommended starting oral dose for the treatment of pathological hypersecretory conditions is 60 mg once daily. Some patients may require divided dosing, and doses up to 100 mg daily and 60 mg twice daily have been administered. No dosage adjustment is necessary in elderly patients, in patients with renal disease, or in patients with mild-to-moderate hepatic impairment. Rabeprazole tablets should not be crushed, chewed, or split; they should be swallowed whole.
Rabeprazole is metabolized by CYP450. In healthy subjects, rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline, diazepam, and phenytoin. The degree of CYP450 inhibition with rabeprazole is similar to that caused by omeprazole. However, like other agents that decrease gastric acid secretion, rabeprazole can decrease the absorption of ketoconazole by approximately 30% as well as increase digoxin absorption by up to 19%. Therefore, patients receiving either of these two agents concomitantly with rabeprazole should be monitored as appropriate.
Rabeprazole is supplied as 20-mg, delayed-release, enteric-coated tablets in bottles of 30 tablets.
Rofecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities. The mechanism of action of rofecoxib is believed to be due to inhibition of prostaglandin synthesis, via inhibition of cyclooxygenase-2 (COX-2). At therapeutic concentrations in humans, rofecoxib does not inhibit the COX-1 isoenzyme.
Rofecoxib is indicated for the relief of signs and symptoms of osteoarthritis, the management of acute pain in adults, and the treatment of primary dysmenorrhea.
Rofecoxib is administered orally. The lowest dose of rofecoxib should be sought for each patient. The recommended starting dose of rofecoxib for the management of osteoarthritis is 12.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 25 mg once daily. The maximum recommended daily dose is 25 mg. Recommended dosing for the management of acute pain and treatment of primary dysmenorrhea is an initial dose of rofecoxib 50 mg once daily. Subsequent doses should be 50 mg once daily as needed. Use of rofecoxib for more than 5 days in the management of pain has not been studied. Rofecoxib may be taken with or without food. The oral suspension of rofecoxib 12.5 mg/5 mL or 25 mg/5 mL may be substituted for rofecoxib tablets 12.5 mg or 25 mg, respectively, in any of the above indications.
Rofecoxib can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Although serious gastrointestinal tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms. Patients should promptly report signs or symptoms of gastrointestinal ulceration or bleeding, skin rash, unexplained weight gain, or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity, eg, nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and flulike symptoms. If these occur, patients should be instructed to stop therapy and seek immediate medical treatment.
Rofecoxib, similar to other nonsteroidal anti-inflammatory drugs (NSAIDs), can diminish the efficacy of angiotensin-converting enzyme (ACE) inhibitors. Concomitant administration of low-dose aspirin with rofecoxib may result in an increased rate of gastrointestinal ulceration or other complications. Rofecoxib can reduce the natriuretic effect of furosemide and thiazide diuretics in some patients. NSAIDs have produced an elevation in lithium plasma levels and a reduction in lithium renal clearance; therefore, if rofecoxib and lithium are to be concomitantly administered, the patient should be monitored for signs of lithium toxicity. Rifampin can decrease the plasma concentration of rofecoxib because it is a potent inducer of hepatic metabolism. Lastly, rofecoxib can increase prothrombin time in patients receiving warfarin therapy.
Rofecoxib is contraindicated in patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
Rofecoxib should be avoided in late pregnancy because it may cause premature closure of the ductus arteriosus.
Rofecoxib is supplied as 12.5- and 25-mg tablets in bottles of 100, 1,000, and 8,000 tablets. Rofecoxib is also available as a suspension containing 12.5 mg/5 mL and 25 mg/5 mL in bottles containing 150 mL of oral suspension.
Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPAR-g). In humans PPAR-g receptors are found in key target tissues for insulin
action, such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-g nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPAR-g-responsive genes also participate in the regulation of fatty acid metabolism.
Rosiglitazone is indicated as monotherapy as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes mellitus. Rosiglitazone is also indicated for use in combination with metformin when diet, exercise, and rosiglitazone or diet, exercise, and metformin alone do not result in adequate glycemic control in patients with type 2 diabetes. For patients inadequately controlled with a maximum dose of metformin, rosiglitazone maleate should be added to, rather than substituted for, metformin. Management of type 2 diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but also in maintaining the efficacy of drug therapy. Prior to initiation of therapy with rosiglitazone maleate, secondary causes of poor glycemic control, eg, infection, should be investigated and treated.
The usual starting dose of rosiglitazone is 4 mg administered either as a single dose once daily or in divided doses twice daily. Rosiglitazone may be taken with or without food. For patients who respond inadequately following 12 weeks of treatment as determined by a reduction in fasting plasma glucose, the dose may be increased to 8 mg administered as a single dose once daily or in divided doses twice daily. In clinical trials, the 4-mg, twice-daily regimen resulted in the greatest reduction in fasting plasma glucose and hemoglobin A1c.
The usual starting dose of rosiglitazone in combination with metformin is 4 mg administered as either a single dose once daily or in divided doses twice daily. The dose of rosiglitazone may be increased to 8 mg/day following 12 weeks of therapy if there is insufficient reduction in fasting plasma glucose. Rosiglitazone may be administered as a single dose in the morning, or divided and administered in the morning and evening.
No dosage adjustments are needed for the elderly. No dosage adjustments are necessary when rosiglitazone is used as monotherapy in patients with renal impairment. Since metformin is contraindicated in such patients, concomitant administration of metformin and rosiglitazone is also contraindicated in patients with renal impairment.
Therapy with rosiglitazone should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels, ALT greater than or equal to 2.5 times the upper limit of normal. Liver enzyme monitoring is recommended in all patients prior to the initiation of therapy with rosiglitazone and periodically thereafter.
In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P-450 enzymes at clinically relevant concentrations. In vitro data demonstrate that rosiglitazone is predominantly metabolized by CYP2C8 and, to a lesser extent, 2C9. Rosiglitazone maleate (4 mg twice daily) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contraceptives (ethynylestradiol and norethindrone), which are predominantly metabolized by CYP3A4.
Adverse reactions possible in patients treated with rosiglitazone are upper respiratory tract infection, headache, fatigue, sinusitis, and diarrhea. There were a small number of patients treated with rosiglitazone maleate who had adverse events of anemia and edema. Overall, these events were generally mild to moderate in severity and usually did not require discontinuation of treatment with rosiglitazone maleate.
Rosiglitazone is supplied as 2- and 4-mg tablets in bottles of 30, 60, 100, and 500 tablets and as 8-mg tablets in bottles of 30, 100, and 500 tablets.
Sirolimus is an immunosuppressive agent produced by Streptomyces hygroscopicus. Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production.
Sirolimus is indicated for the prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids.
Sirolimus is administered orally once daily. The initial dose of sirolimus should be administered as soon as possible after transplantation. For de novo transplant recipients, a loading dose of sirolimus of three times the maintenance dose should be given. A daily maintenance dose of 2 mg is recommended for use in renal transplant patients, with a loading dose of 6 mg. The initial dosage in patients 13 years of age or older who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m2 per day. The loading dose should be 3 mg/m2 per day. It is recommended that the maintenance dose of sirolimus be reduced by approximately one third in patients with hepatic impairment; however, it is not necessary to modify the sirolimus loading dose.
To minimize the variability of exposure to sirolimus, this drug should be taken consistently with or without food. Grapefruit juice reduces the CYP3A4 metabolism of sirolimus; therefore, it must not be administered with sirolimus or used for dilution. In addition, it is recommended that sirolimus be taken 4 hours after cyclosporine oral solution (Neoral, SangCya) and/or cyclosporine capsules (Neoral).
The daily dose of sirolimus should be administered in 2 oz of water or orange juice. A detailed description of the patient administration technique is included in the package insert information and should be reviewed prior to dispensing sirolimus.
Sirolimus is a known substrate of both CYP3A4 and P-glycoprotein. Since sirolimus is extensively metabolized by the CYP3A4 isoenzyme in the gut wall and liver, its absorption and subsequent elimination may be influenced by drugs that affect CYP3A4. Drugs that may increase sirolimus blood concentrations include verapamil, nicardipine, fluconazole, itraconazole, clarithromycin, erythromycin, trole- andomycin, cisapride, metoclopramide, cimetidine danazol, HIV protease inhibitors, and bromocriptine. Drugs that may decrease sirolimus levels include carbamazepine, phenobarbital, phenytoin, rifampin, rifabutin, and rifapentine. Although this list is not all-inclusive, it would be prudent to review a patient’s current medications at the time of initiation of sirolimus therapy for agents known to affect CYP3A4 by induction or inhibition.
Women of childbearing potential should be informed of the potential risks during pregnancy and that they should use effective contraception prior to initiation of sirolimus therapy and for 12 weeks after sirolimus therapy is completed. Immunosuppressants, such as sirolimus, may affect response to vaccination. Therefore, during treatment with sirolimus, vaccination may be less effective and the use of live virus vaccines should be avoided.
Adverse reactions that have occurred during sirolimus therapy are hypercholesterolemia, hypertension, rash, acne, anemia, leukopenia, thrombocytopenia, hypokalemia, fever, and diarrhea. The elevations of cholesterol, and triglycerides and decreases in platelets and hemoglobin occurred in a dose-related manner in patients receiving sirolimus.
Sirolimus oral solution is supplied as a concentration of 1 mg/mL in cartons containing either 60 or 150 mL of sirolimus oral solution. Sirolimus oral solution is also supplied in cartons containing 30 unit-of-use laminated aluminum pouches of 1, 2, and 5 mL. All unit-of-use pouches contain the 1-mg/mL concentration sirolimus oral solution. Patients should also be informed that sirolimus oral solution should be stored in the refrigerator and protected from light; however, pouches and bottles may be kept at room temperature for short periods of time (several days, but not more than 30).
Temozolomide is indicated for the treatment of adult patients with refractory anaplastic astrocytoma. Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound MTIC. The cytotoxicity of MTIC is thought to be primarily the result of alkylation of DNA.
The initial dosage of temozolomide is 150 mg/m2 orally once daily for 5 consecutive days per 28-day treatment cycle. The dosage of temozolomide must be adjusted according to nadir neutrophil and platelet counts in the previous cycle and neutrophil and platelet counts at the time of initiating the next cycle.
Capsules of temozolomide should not be opened. If capsules are opened or damaged, rigorous precautions should be taken with the contents to avoid inhalation or contact with the skin or mucous membranes.
In clinical trials, the most frequently occurring adverse effects were nausea and vomiting. These were usually either self-limiting or readily controlled with standard antiemetic therapy. In addition
fatigue and hematologic adverse effects appear to be clearly drug-related.
Temozolomide is contraindicated in patients who have a history of hypersensitivity reaction to DTIC, since both drugs are metabolized to MTIC.
Temozolomide is supplied as 5-, 20-, 100-, and 250-mg capsules in bottles containing 5 or 20 capsules.
Zaleplon (Sonata)
Wyeth-Ayerst Laboratories
Zaleplon is a nonbenzodiazepine hypnotic agent of the pyrazolopyrimidine class. Zaleplon selectively binds to type 1 benzodiazepine receptors at the GABAA receptor complex in a manner similar to zolpidem. Zaleplon is indicated for the short-term treatment of insomnia. Hypnotics should generally be limited to 7 to 10 days of use, and reevaluation of the patient is recommended if they are to be taken for more than 2 to 3 weeks. Zaleplon should not be prescribed in quantities exceeding a 1-month supply.
The recommended dose of zaleplon is 10 mg at bedtime for adults, and 5 mg at bedtime is recommended for elderly patients and those with liver disease. Zaleplon is not recommended for patients with severe liver impairment. Advise your patients that zaleplon should be taken immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep. As with all sedative/hypnotic agents, taking zaleplon while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness. A 20-mg dose may be considered for any patient who does not benefit from a smaller dose of zaleplon. Doses larger than 20 mg have not been evaluated adequately and are not recommended.
Zaleplon can potentiate the CNS-impairing effects of ethanol, and patients should be warned to avoid the concomitant use of ethanol and zaleplon. An additive reduction in alertness and psychomotor performance has been observed 2 to 4 hours after concomitant administration of zaleplon and imipramine or thioridazine in single-dose studies. While potential additive CNS depression is a possible mechanism of interaction with zaleplon, there is a possibility of alterations in zaleplon metabolism by concomitantly administered medications. Zaleplon is metabolized primarily by aldehyde oxidase and to a lesser extent by CYP3A4. Rifampin, a potent enzyme inducer, can reduce zaleplon peak plasma concentrations and area under the curve by up to 80%. Induction of the CYP3A4 isoenzyme by rifampin or other inducers could reduce the plasma concentrations and efficacy of zaleplon. Larger zaleplon doses may be needed in patients receiving drugs that induce CYP3A4. An additional interaction precaution is with concomitant administration of cimetidine. Since cimetidine is a weak inhibitor of aldehyde oxidase and an inhibitor of CYP3A4, it can increase the plasma concentrations of zaleplon by as much as 85%. Therefore, a lower 5-mg dose of zaleplon is recommended for patients receiving cimetidine.
The most common adverse effects experienced by patients in clinical trials receiving zaleplon were headache, dizziness, myalgia, and nausea.
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative/hypnotic drugs, including zaleplon. Because some important adverse effects of zaleplon appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly.
Zaleplon is supplied as 5- or 10-mg capsules in bottles containing 100 capsules.
Zanamivir (Relenza)
Glaxo Wellcome Inc.
Zanamivir is classified as a neuraminidase inhibitor. The proposed mechanism of action of zanamivir is inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release.
Zanamivir is indicated for the treatment of uncomplicated acute illness caused by influenza virus in adults and adolescents 12 years and older who have been symptomatic for no more than 2 days.
Zanamivir is intended for administration to the respiratory tract by oral inhalation only, using the Diskhaler device provided. The recommended dose of zanamivir for the treatment of influenza is two inhalations, one 5-mg blister per inhalation for a total dose of 10 mg twice daily approximately 12 hours apart for 5 days. Two doses should be taken on the first day of treatment whenever possible, provided there is at least 2 hours between doses. On subsequent days, doses should be about 12 hours apart at approximately the same time each day. There are no data on the effectiveness of treatment with zanamivir when initiated more than 2 days after the onset of signs or symptoms of influenza.
Patients scheduled to use an inhaled bronchodilator at the same time as zanamivir should use their bronchodilator before taking zanamivir. However, safety and efficacy have not been demonstrated in patients with underlying chronic pulmonary disease. In particular, zanamivir has not been shown to be effective, and may carry risk, in patients with severe or decompensated chronic obstructive pulmonary disease or asthma.
Patients should be instructed in use of the delivery system. Instructions should include a demonstration whenever possible. For the proper use of zanamivir, the patient should read and follow carefully the accompanying Patient’s Instructions for Use. Patients should also be advised to complete the entire 5-day course of treatment even if they start to feel better sooner. Also of note, zanamivir has not been shown to reduce the risk of transmission of influenza to others.
Overall, zanamivir is well tolerated, however the following adverse effects have been reported during clinical trials with zanamivir: headaches, diarrhea, nausea, vomiting, sinusitis, ear, nose, and throat infections, and dizziness.
Zanamivir is supplied as a circular double-foil pack, Rotadisk, containing four blisters of the drug. Five Rotadisks are packaged in a white polypropylene tube. The tube is packaged in a carton with one Diskhaler inhalation device.
