Pocket Drug Guide

Posts Tagged ‘Active Ingredient’

Brand Name: Malarone
Active Ingredient: atovaquone and proguanil hydrochloride
Indication: Treatment and prevention of P. falciparum malarial infection in adults and children
Company Name: Glaxo Wellcome Inc.
Availability: Approved by FDA on July 14, 2000

Introduction

The antimalarial drug atovaquone was developed in the 1980s and was shown to be effective when used alone, but a recurrence of malaria was observed in some patients over time. However, when combined with proguanil, an older antimalarial drug, a 98% cure rate could be achieved.

On July 14, 2000, the FDA approved the combination of atovaquone and proguanil to prevent and treat malaria in adults and children. Produced under the trade name Malarone, the drug duo is manufactured by Glaxo Wellcome Inc., which expects Malarone to be available by mid-August 2000.

For adults using Malarone for malaria prevention, the recommended dosage is one tablet daily (250 mg atovaquone and 100 mg proguanil) starting one or two days prior to entering a malaria-endemic area, one tablet a day while in the area, and one tablet a day for only seven days after return. For children who weigh less than 88 pounds, a lower-dose pediatric tablet is available. For adult patients with acute malaria, four tablets are administered as a single dose once daily for three days. Pediatric dosages for the treatment of malaria are adjusted by body weight.

How It Works

Atovaquone and proguanil interfere with two different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication. Atovaquone is a selective inhibitor of Plasmodium falciparum mitochondrial electron transport. Proguanil primarily exerts its effect by means of the metabolite cycloguanil, a dihydrofolate reductase inhibitor. Inhibition of dihydrofolate reductase in the malaria parasite disrupts deoxythymidylate synthesis.

Malarone: Clinical Study Results

Clinical trials leading to U.S. approval of Malarone for prevention of malaria caused by P. falciparum involved more than 400 adults and children (children weighing at least 24 pounds) in malaria-endemic areas where subjects were treated for 10-12 weeks (refs. 1, 2). These studies showed that Malarone was 98% effective in preventing malaria. Clinical trials for the treatment of acute, uncomplicated P. falciparum malaria involved 521 adults and children (children weighing at least 24 pounds) (ref. 1). These studies showed Malarone was 98.7% effective.

What the Patient Should Know

The most common adverse events in people taking Malarone for prevention of malaria included headache and abdominal pain and occurred at rates comparable to placebo. The most common adverse events reported in over 10% of patients taking Malarone for treatment of malaria were abdominal pain, nausea, vomiting and headache in adults and vomiting in children.

Patients with severe malaria are not candidates for oral therapy. Malarone has not been evaluated for the treatment of severe malaria, including cerebral malaria.

Malarone should be taken at the same time each day with food or a milky drink.

Brand Name: Rapamune
Active Ingredient: sirolimus
Indication: The prevention of acute kidney rejection following transplantation
Company Name: Wyeth-Ayerst Laboratories
Availability: By prescription only

Introduction

The U.S. Food and Drug Administration’s (FDA) Subcommittee of the Antiviral Drugs Advisory Committee on Immunosuppressive Drugs voted unanimously 27 July 1999 that Rapamune® (sirolimus) is safe and effective for the prevention of acute kidney rejection following transplantation. If final approval is ultimately given by the FDA, Rapamune would be the first of a new class of immunosuppressive agents developed to treat transplant patients. Rapamune is a product of Wyeth-Ayerst Laboratories, the pharmaceutical division of American Home Products Corporation.

Kidney transplantation is the most common type of transplant procedure in the U.S., with over 12,000 transplants occurring in 1998. To help minimize the risk of organ rejection, transplant patients are given a life-long regimen of immunosuppressive agents. These drugs are intended to lower the body’s normal immune response allowing the transplanted organ to remain functional.

Many patients require retransplants in part because of organ failure due to toxicities; this need for repeat organ transplants only compounds the organ shortage. For example, there are more than 40,000 patients in the U.S. awaiting kidney transplants. However, only about 12,000 kidneys were available for use in 1998. These organ shortages have increased the importance of organ transplants being successful and the need for new therapies that can help decrease the incidence of rejection episodes.

Rapamune (sirolimus) was first developed as a potential antifungal agent, called rapamycin. When testing the antifungal properties of rapamycin in the 1970′s, researchers discovered that it caused suppression of the immune system and abandoned it as an antifungal agent. The drug then demonstrated the ability to halt the growth of cancerous tumors, but attempts to develop an intravenous formula of rapamycin proved futile. In the 1980′s, researchers focused their attention on rapamycin’s immunosuppressive properties. Subsequent clinical trials demonstrated that rapamycin could more effectively and safely lower the risk of chronic rejection of kidney transplants.

How it Works

When an organ is transplanted, the recipient’s immune system recognizes the new organ as foreign and attacks it. The attack causes a build-up of scar tissue, associated with chronic rejection, on the transplanted organ. Rapamune (sirolimus) reduces the risk of chronic rejection by suppressing the immune system, hence weakening its attack.

Rapamune (sirolimus): Clinical Study Results

Two clinical trials, one conducted in the United States and one involving patients from nine countries, demonstrated Rapamune’s efficacy versus standard treatment and versus placebo.

The U.S. study was randomized, double-blinded, comparative, and race-stratified. It involved 38 centers and included 719 kidney transplant patients. Patients were randomized to receive a combination of cyclosporin, a steroid, and Rapamune 2 mg or 5 mg or the standard treatment of cyclosporin, a steriod, and azathioprine. The primary endpoint was efficacy failure. 18.7% and 16.8% of the patients receiving 2 mg and 5 mg of Rapamune, respectively, reached endpoint; whereas, 32.3% of the patients receiving standard therapy experienced endpoint.

The second study included 576 patients and compared Rapamune (sirolimus) to placebo. Except for the control group that received cyclosporin, a steroid, and placebo, patients in the international trial received the same drug treatments as the patients in the above-mentioned trial. 30%, 25.6%, and 47.7% of patients who were administered Rapamune 2 mg, Rapamune 5 mg, and placebo, respectively, experienced endpoint. The large differences in the results of the U.S. trial and the international trial could be attributable to the differing methodologies of the studies. The U.S. study eliminated high-risk patients that may have been included in the international trial.

What the Patient Should Know

Rapamune (sirolimus) is administered orally (2 mg or 5 mg) in combination with cyclosporin and a steriod to avoid transplant rejection. Patients receiving this treatment are under strict medical supervision.

Brand Name: Locilex 1% Topical Cream
Active Ingredient: pexiganan acetate
Indication: Topical antibiotic therapy of infected diabetic ulcers
Dosage Form(s): Topical Cream
Company Name: SmithKline Beecham Pharmaceuticals and Magainin Pharmaceuticals Inc.

Introduction

Among the most common and severe complications of diabetes mellitus is the development of topical skin ulcers. These often occur at pressure points and at the extremities, and infected diabetic foot ulcers often result in limb loss. Poor peripheral blood circulation limits the body’s natural defenses against infection and slows the overall healing process. Aggressive wound care, including rigorous debridement and antibiotic therapy, are the cornerstones of management. Increasingly, however, these ulcers are colonized with pathogens that are resistant to traditional antibiotics. Furthermore, poor regional circulation often compromises attaining minimum inhibitory concentrations of antibiotics at the infected site. Consequently, topical application of an antibiotic could provide the therapeutic levels required to control local infection.

Locilex (pexiganan acetate) is a novel antibiotic designed for topical administration that appears to demonstrate activity against common pathogens associated with infected diabetic ulcers.

How It Works

Pexiganan is a synthetic 22-amino acid peptide with a broad spectrum of antimicrobial activity. It is a synthetic analog of magainin-2, which is a 23-amino acid peptide that was isolated from the skin of the African clawed frog. Pexiganan’s mechanism is similar to that of other magainins; it is thought to exert its bactericidal effect on susceptible organisms by altering the permeability of the cell membrane. Bacterial cell membranes are composed of negatively charged phospholipids that attract and bind the positively charged helices of the magainin peptides. These peptides do not seem to interact with bacterial receptors or enzymes.

Locilex: Clinical Study Results

Pexiganan acetate (Locilex) has been found to have a broad spectrum of antimicrobial activity against many gram-positive and gram-negative aerobic and anaerobic bacteria and certain species of fungi.

In vitro, 91% of aerobic strains of bacteria were susceptible to pexiganan, similar to the 91% for ofloxacin and 92% for ciprofloxacin. Only enterococci required the highest concentrations of pexiganan for eradication. Of the anerobes tested, 97% were susceptible to pexiganan. Thirty percent of candida isolates were inhibited by the drug.

In vivo studies have shown a 5-log reduction in the numbers of Pseudomonas aeruginosa in swine skin wounds and a 4-log reduction in perineal skin flora on human skin following topical application. Several large-scale clinical studies have been completed evaluating the drug in the treatment of infected diabetic foot ulcers. These were designed to compare the efficacy of pexiganan to that of the fluoroquinolone ofloxacin, which is recognized as being a standard of antibiotic therapy for infected diabetic ulcers. In one study of 490 diabetics treated for 14-28 days, clinical response rates (improvement or resolution) were similar for pexiganan and ofloxacin, ranging from 84-93%; the frequencies of osteomyelitis and amputations were similar between groups. The cream was somewhat better tolerated than oral ofloxacin. In another study of 835 patients, the overall pathogen eradication rates were 66% for pexiganan compared to 82% for ofloxacin. However, clinical cures occurred in many pexiganan-treated patients who did not have microbial eradication, indicating that microbial eradication does not appear to be needed for a positive clinical response.

What The Patient Should Know

The use of a topical antibiotic may be more convenient than an oral dosage form for some patients, especially the elderly who have difficulty swallowing. While guidelines for the dosing and administration of pexiganan have not yet been formalized, it is certain that good wound debridement will be important in the effective use of this drug.

Brand Name: Tamiflu
Active Ingredient: oseltamivir phosphate
Indication: Treatment of influenza A and B
Company Name: Hoffmann-La Roche Inc. and Gilead Sciences, Inc.
Availability: Approved for marketing in the US in October 1999

Introduction

Some 40 million Americans develop the flu every year, putting about 300,000 in the hospital. Up to 40,000 people die from influenza or its complications annually. Moreover, hospitalization and deaths due to the flu are increased among the elderly and those with high-risk medical conditions. The economic costs of the flu are high as well: some $14.6 billion due to lost wages, decreased productivity, and physician visits.

Arriving just in time for this year’s flu season, Tamiflu (oseltamivir phosphate) is the first neuraminidase inhibitor available in pill form. It is indicated for the treatment of uncomplicated acute illness due to infection with influenza A and B (which includes all common strains of the virus) in adults who have been symptomatic for no more than two days. Unlike over-the-counter medications that treat only the symptoms of the flu, Tamiflu actually targets the influenza virus and stops it from replicating. The recommended oral dose is 75 mg twice daily for five days.

How It Works

The neuraminidase protein is one of two major surface structures on the influenza virus and is virtually the same from one common strain of influenza to the next. The influenza virus needs neuraminidase to replicate and spread to other cells. In vitro studies showed that Tamiflu works by binding to the neuraminidase site and inhibiting its action, thus preventing replication of the influenza virus and its ability to spread from cell to cell.

Tamiflu (oseltamivir phosphate): Clinical Study Results

The efficacy of Tamiflu was demonstrated in two phase III double-blinded placebo-controlled trials, one conducted in the US and one outside the US. Eligible patients had a fever of more than 100 degrees F and at least one respiratory symptom (cough, nasal symptoms, or sore throat) and at least one systemic symptom (myalgia, chills/sweats, malaise, fatigue, or headache), and influenza known to be circulating in the community. Of 849 influenza-infected patients, 95% had influenza A, 3% had influenza B, and 2% had an unknown type.

Tamiflu administration commenced within 40 hours of onset of symptoms. Subjects participating in the trials were required to assess their symptoms as none, mild, moderate, or severe. Time to improvement was defined as the interval between the initiation of treatment to the time when all symptoms could be described as none or mild. In both studies, influenza-infected patients who received 75 mg of Tamiflu twice daily for five days showed a 1.3 day reduction in time to improvement of symptoms when compared to patients receiving placebo. The results were similar among men and women and in the elderly.

Recent studies have demonstrated that Tamiflu may be able to prevent infection with influenza A and B. However, the drug is not approved for this indication at this time.

What the Patient Should Know

Nausea and vomiting were the most common adverse events reported in patients taking Tamiflu, and to a lesser extent, bronchitis, insomnia, and vertigo. These events were generally mild and transient. Patients are advised to begin Tamiflu treatment as soon as possible after the initial appearance of symptoms. Finally, Tamiflu is not a substitute for a flu shot. Patients should continue receiving an annual flu shot according to immunization guidelines.

Brand Name: Sonata
Active Ingredient: zaleplon
Indication: Treatment of short-term insomnia
Company Name: Wyeth-Ayerst Laboratories, Inc.
Availability: Approved for marketing in the US on 16 August 1999

Introduction

According to the National Sleep Foundation, insomnia affects nearly 83 million Americans; however, many people avoid sleep aids for fear of next-day drowsiness. Sonata has been shown to greatly reduce the incidence of next-day effects. It is the first in a new class of nonbenzodiazepine (pyrazolopyrimidine) compounds that possess a mechanism of action that differs from those of currently used sleep aids.

How It Works

Sonata (zaleplon) interacts with the GABA-BZ receptor-chloride channel macromolecular complex. Unlike other hypnotic agents, it remains at the binding site only until sleep is initiated. At this point, it is rapidly eliminated, allowing the natural sleep process to occur. The effects of Sonata last for four hours. This enables the patient to take Sonata in the middle of the night and not experience severe next-day effects.

Sonata (zaleplon): Clinical Study Results

Sonata was studied in 2,800 patients experiencing transient insomnia or chronic insomnia. Three studies focused on 1,019 elderly patients, who ranged in age from 65 to 85 years. A double-blind, parallel-group trial, conducted in a sleep laboratory, examined the effects of Sonata in patients with transient insomnia. The study, which compared Sonata 5 mg and 10 mg with placebo, found the 10 mg dose to be superior to placebo in decreasing latency to persistent sleep (LPS), a polysomnographic measure of time to sleep onset (TSO).

Several studies examining patients with chronic insomnia were conducted. Three double- blind, parallel-group outpatient studies, one lasting 2 weeks and the other two lasting 4 weeks, compared the effects of 5 mg, 10, mg, and 20 mg Sonata with placebo on TSO. Sonata 10 mg and 20 mg were consistently superior to placebo for TSO; whereas, Sonata 5 mg was less consistently effective than 10 mg and 20 mg. Sleep latency with the 10 mg and 20 mg doses was 10-20 minutes (15-30%) less than with placebo. Five double-blind, parallel-group sleep laboratory studies, varying in duration from one night to 28 days, were conducted. Overall, the studies demonstrated Sonata 10 mg and 20 mg as superior over placebo in reducing latency to persistent sleep (LPS) on the first 2 nights of treatment. A reduction in LPS relative to baseline was observed for all treatment groups at later time points. As a result, a significant difference from placebo was not observed beyond 2 nights. Trials focusing on elderly patients were conducted, but no significant difference in effect was observed between elderly patients and other adult patients.

What the Patient Should Know

The most common adverse events were headache, drowsiness, and dizziness. There was no evidence of memory or psychomotor impairment four or more hours after administration of Sonata. Until the patient is aware of whether or not he/she will experience carryover effects, extreme caution should be taken when completing tasks that require complete alertness. Alcohol should not be consumed while taking Sonata, as it increases the side effects of the drug. The recommended dose is 5 mg for elderly patients and 10 mg for younger adults.

Brand Name: Chirocaine
Active Ingredient: levobupivacaine
Indication: Chirocaine induces local or regional anesthesia for surgery and obstetrics. It is also indicated for post-operative pain management.
Company Name: Purdue Pharma L.P.
Availability: Approved for marketing in the US on 5 August 1999

Introduction

The active ingredient in Chirocaine (levobupivacaine) is an enantiomer of buvipacaine, a long-acting anesthetic. Currently, buvipacaine is the most commonly used local anesthetic in obstetrics; however, it is associated with potentially fatal cardiotoxicity. Clinical studies have shown that the risk of cardiotoxicity is not as great with Chirocaine. Chirocaine (levobupivacaine) is indicated for local or regional anesthesia in surgery and for post-operative pain management. More specifically, Chirocaine is to be used as surgical anesthesia for epidurals, peripheral neural blockades, and local infiltration. Chirocaine (levobupivacaine) can be used to manage pain by continuous epidural infusion or intermittent epidural blockage, continuous or intermittent peripheral neural blockage, and local infiltration.

How It Works

Chirocaine (levobupivacaine) blocks the generation and conduction of nerve impulses through a mechanism shared with most local anesthetics. Chirocaine produces an anesthetic effect by increasing the threshold for electrical excitation in the nerve. This can be achieved by slowing the propagation of the nerve impulse and by reducing the rate of rise of the action potential.

Chirocaine (levobupivacaine): Clinical Study Results

Chirocaine (levobupivacaine) was studied as a local anesthetic in adults, as an epidural block in surgical patients, in peripheral neural blockade, and for post-operative pain control. Most of the published clinical data involved the use of Chirocaine as an epidural block for surgical patients. Two clinical studies examined Chirocaine (levobupivacaine) administered epidurally in patients undergoing cesarean section. A randomized, double-blind trial compared Chirocaine and bupivacaine, 0.50%, in 62 patients. The mean time to sensory block measured at T4 to T6 was 10 +/- 8 minutes and 6 +/- 4 minutes for Chirocaine and bupivacaine, respectively. The mean duration of sensory and motor block was 8 +/- 1 hours and 4 +/- 1 hours for Chirocaine and 7 +/- 1 and 4 +/- 1 hours for bupivacaine. Blocks adequate for surgery were attained in 94% of Chirocaine patients and 100% of bupivacaine patients. The second trial was bupivacaine-controlled and included 62 patients undergoing cesarean section. The mean time to onset of T4 to T6 sensory block was 10 +/- 7 minutes for Chirocaine (levobupivacaine) and 9 +/- 7 minutes for bupivacaine. Bilateral blocks adequate for surgery were achieved in 94% and 91% of Chirocaine and bupivacaine patients, respectively.

The epidural administration of Chirocaine (levobupivacaine) during labor and delivery was compared to bupivacaine in a randomized, double-blind trial. Intermittent injections of Chirocaine 0.25% or bupivacaine 0.25% via an epidural catheter were administered to 68 patients. The median duration of pain relief was 49 minutes for Chirocaine patients and 51 minutes for bupivacaine patients. Following the first top-up injections, 91% of Chirocaine patients and 90% of bupivacaine patients received relief from pain.

Epidural administration of Chirocaine (levobupivacaine) was examined in 85 patients undergoing lower limb or major abdominal surgery. This randomized, double-blind study compared Chirocaine 0.5% and 0.75% to bupivacaine. The mean time to onset of sensory block was 14 +/- 6 minutes for Chirocaine and 14 +/- 10 minutes for bupivacaine in abdominal surgery patients. The time to complete regression of the block was 551 +/- 88 minutes for Chirocaine patients and 506 +/- 71 minutes for bupivacaine patients.

What the Patient Should Know

Adverse events that occurred in patients treated with Chirocaine (levobupivacaine) were no different from those associated with other amide-type local anesthetics. The majority of these adverse events due to this class of drugs are related to excessive plasma drug levels as a result of overdose, unintentional intravascular injection, or slow metabolic breakdown. The most common adverse events were hypotension, nausea, fever, and vomiting. As with other anesthetics, the patient may experience transient loss of sensation and motor activity in the anesthetized part of the body after proper administration of regional anesthesia. Nursing mothers should be cautious, since most local anesthetics are distribute into human milk. Although the presence of Chirocaine in human milk has not been well studied, small amounts of Chirocaine (levobupivacaine) were detected in the pups of rats after the drug was administered to the nursing mother.

Brand Name: Doxil
Active Ingredient: doxorubicin HCl liposome injection
Indication: Treatment of metastatic ovarian cancer in patients with the disease that is refractory to both paclitaxel- and platinum-based chemotherapy
Company Name: ALZA Pharmaceuticals
Availability: Not approved for marketing as of Aug 99

Introduction

Doxil was previously approved for the treatment of AIDS-related Kaposi’s sarcoma in patients with disease that has progressed in spite of prior chemotherapy or in patients who are unable to tolerate therapy. On June 28, 1999, Doxil was granted accelerated approval for a new indication, for treatment of patients with metastatic ovarian cancer who did not respond to paclitaxel- and/or platinum-based chemotherapy. Full approval is expected once the time to progression and survival endpoint data are obtained from an ongoing Phase III, 400-patient trial.

How it Works

Doxorubicin HCl is a cytotoxic anthracycline antibiotic associated with a hydrogen chloride radical. The molecule is encapsulated in STEALTH liposomes, which are formulated with surface-bound methoxypolyethylene glycol (MPEG). The STEALTH liposomes that surround Doxil allow the drug to circulate in the blood for extended periods of time. It is believed that Doxil’s effectiveness is due to its small size, which enables the drug molecules to enter the vasculature of tumors. Once inside the tumor, Doxil binds to DNA and inhibits nucleic acid synthesis.

Doxil: Clinical Study Results

One hundred and forty-six patients were included in three open-label studies. All patients had metastatic ovarian carcinoma that was refractory to paclitaxel- and platinum-based chemotherapy. Patients were classified as having refractory carcinoma if the disease progressed during treatment or within six months of treatment completion. All the participants in the three studies were administered 50mg/m2 infused over one hour every three to four weeks for three to six cycles. The response rate of the refractory patients was the primary efficacy endpoint. Response was assessed using the Southwest Oncology Group (SWOG) criteria. Each response assessment required confirmation four weeks after the initial observation. Secondary efficacy parameters included time to response, duration of response, and time to progression. The response rates for three studies were 22.2% (95% confidence interval [CI]; 8.6% – 42.3%), 17.1% (95% CI; 9.7% – 26%), 0% (95% CI; 0% – 9.7%). The combined response rate of the three studies was 13.8% (95% CI; 8.1% – 19.3%). Data from the three studies were combined to determine the median time to progression, the median time to response, and the duration of response (15.9 weeks, 17.6 weeks, and 39.4 weeks, respectively).

What the Patient Should Know

The following adverse events were reported during the above clinical studies: hand-foot syndrome, stomatitis, and neutropenia. Nausea, vomiting, tiredness, weakness, rash, and mild hair loss should be reported to the patient’s physician.

Brand Name: Ferrlecit
Active Ingredient: sodium ferric gluconate complex sucrose injection
Indication: iron deficiency in patients undergoing chronic hemodialysis who are receiving supplemental erythropoietin therapy
Company Name: Schein Pharmaceutical, Inc.

Introduction

Ferrlecit is used to increase the total body content of iron in patients undergoing chronic hemodialysis who are receiving supplemental erythropoietin therapy. Iron is crucial for normal hemoglobin synthesis and an important component of DNA metabolism and synthesis and many enzymatic processes. Erythropoietin therapy increases the production of red blood cells and iron utilization. This increase in iron utilization can cause iron deficiency in hemodialysis patients.

Ferrlecit: Clinical Study Results

Two studies were conducted to determine the safety and efficacy of Ferrlecit in patients undergoing hemodialysis and on erythropoietin therapy. The first study was multicenter, randomized, and open-label in design and included an historical control group. Patients initially received 25 mg Ferrlecit and were then randomized to receive either 62.5 mg of Ferrlecit over 30 minutes (n = 39) or 125 mg of Ferrlecit over 60 minutes (n = 44). Eight doses were administered during sequential dialysis sessions. The primary endpoint was a change in hemoglobin from baseline to the last available observation through day 40. Patients in the high-dose Ferrlecit group demonstrated the greatest increases in hemoglobin (1.1 g/dl) and hematocrit (3.6%) over baseline (p-value vs. 500 mg group and the historical control group < 0.01). The results were similar between the low-dose group and the oral iron group for changes in hemoglobin and hematocrit levels, 0.3 g/dl vs. 0.4 g/dl and 1.4% vs. 0.8%, respectively.

A single-center, non-randomized, open-label, historically-controlled study was also carried out. Ferrlecit administration was the same as the above study. Again, Ferrlecit proved to be more effective than oral iron administration. Patients in the Ferrlecit group experienced a significant (p < 0.001 from baseline by the paired t-test method) increase in hemoglobin (1.3 g/dl) and hematocrit (3.8%) levels over the control group (0.4 g/dl; 0.8%).

What the Patient Should Know

Some possible adverse events associated with use of Ferrlecit are headache, abdominal pain, fatigue, and fever.

Brand Name: Pletal
Active Ingredient: cilostazol
Approved uses: the reduction of symptoms of intermittent claudication, as indicated by an increase in walking distance
Dosage Form(s): Tablets (50 mg and 100 mg)
Company Name: Otsuka America Pharmaceutical, Inc.
Availability: Prescription only

Introduction

Treatment options for intermittent claudication – a severe pain, aching or cramping in the legs that occurs with walking – include exercise regimens, surgery, and pharmacological therapy. Until recently the only medication available for the treatment of intermittent claudication has been Trental® (pentoxifylline). Pletal (cilostazol) provides a new option for improving the symptoms of this condition. This drug is the first to be approved for this indication in more than 15 years.

Intermittent claudication results from “peripheral arteriosclerotic vascular disease” – a condition more commonly known as atherosclerosis or hardening of the arteries. Atherosclerosis occurs when deposits of fatty substances build up, in this case in the legs, leading to an inadequate blood supply to the leg muscles.

Intermittent claudication affects several million, predominantly elderly, Americans. It can greatly impair their ability to walk without considerable discomfort and can seriously affect their ability to exercise or even engage in ordinary activities of daily life. Standard effective treatments have included intensive exercise regimens, and drug treatments, i.e., pentoxifylline (Trental), and under certain circumstances, re-vascularization procedures (operations to open the leg arteries or provide a replacement artery).

How It Works

The mechanism of the effects of Pletal (cilostazol) on the symptoms of intermittent claudication is not fully understood. Pletal and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation.

Pletal (cilostazol): Clinical Study Results

The clinical efficacy of Pletal (50 mg or 100 mg twice daily) was evaluated in eight large, randomized, placebo-controlled, double-blind studies of 12 to 24 weeks’ duration. The ability of Pletal (cilostazol) to improve walking distance in patients with stable intermittent claudication was the main outcome measure. When compared to placebo, patients receiving Pletal experienced statistically significant improvements in walking distance. In some patients the beneficial effect was seen in two to four weeks.

In these trails, the range of improvement in maximal walking distance in patients receiving Pletal 100 mg twice a day ranged from 28% to 100%. The range is expressed as the mean change from baseline walking distance. Conversely, the placebo group experienced a change of -10% to 30%. In six of the trials, patients were asked to complete a questionnaire to assess the impact of the drug on walking distances. A pooled analysis of the results of the questionnaire showed that patients taking Pletal (cilostazol) reported improvements in both walking distance and speed when compared to placebo. These improvements were seen in subgroups defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use of beta blockers or calcium channel blockers.

Pletal (cilostazol) is metabolized extensively by cytochrome P-450 isoenzymes, primarily CYP3A4 with CYP2C19 involved to a lesser extent. Coadministration of Pletal with drugs that alter the activity of these P-450 enzymes should be done cautiously. It is recommended that drinking grapefruit juice, which inhibits CYP3A4, be avoided.

At this time, there is no information with respect to the efficacy and safety of the concurrent use of Pletal and clopidogrel (Plavix®). Clopidogrel is a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Studies of concomitant use of Pletal and clopidogrel are planned.

What The Patient Should Know

Pletal (cilostazol) should not be used in patients who have, or develop, congestive heart failure. Pletal and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs that exert this pharmacologic effect have caused decreased survival in patients with congestive heart failure.

The long-term effects of phosphodiesterase III inhibitors in patients without congestive heart failure are unknown. Among patients who were participating in the 3-6 month placebo-controlled studies, the death rate was similar in both groups and less than 1%. These patients were relatively stable and had not had a recent heart attack or stoke and had no rest pain or other signs of rapidly progressing disease. However, there is no data on long-term risk or risk in patients with more severe underlying heart disease.

Pletal (cilostazol) should be taken at least one half-hour before or two hours after breakfast or dinner.

Certain foods and medications can affect plasma levels of Pletal in the body. The latter include erythromycin (Erythrocin ®), ketoconazole (Nizoral ®), itraconazole (Sporanox ®), diltiazem (Cardizem ®), and omeprazole (Prilosec ®). This list is not complete and the patient should discuss any current or new medications with their doctor or pharmacist.

Pletal (cilostazol) should not be taken with grapefruit juice.

Side effects of Pletal that have been reported include headache, diarrhea, abnormal stools, increased heart rate, and palpitations.

Brand Name: Zyvox
Active Ingredient: linezolid
Indication: Being studied for the treatment of community-acquired pneumonia, hospital-acquired pneumonia, complicated and uncomplicated skin and soft tissue infections, and bacteremia caused by gram-positive bacteria.
Company Name: Pharmacia & Upjohn Inc.
Availability: Prescription only

Introduction

The oxazolidinones are the first new class of antibiotics to be introduced in over 30 years and Zyvox is being developed as the forerunner of this class. Zyvox has a unique mechanism of action and it has demonstrated in vitro activity against bacteria resistant to other antibiotics, including methicillin-resistant Staphylococci (MRS), multi-resistant strains of S. pneumoniae and vancomycin-resistant enterococci (VRE). Zyvox is currently in Phase III trials and registration applications are expected to be submitted by the end of 1999.

Zyvox: How It Works

Zyvox (linezolid) inhibits initiation of protein synthesis by preventing the formation of the fmet- tRNA:mRNA:30S subunit ternary complex. It has also been shown that oxazolidinones bind to the 50S subunit in a region shared with the peptidyl transferase inhibitor chloramphenicol. Oxazolidinones are not peptidyl transferase inhibitors and it is not known which specific ribosome reaction is inhibited by 50S subunit binding.

Clinical Study Results

An open-label, noncomparative Phase II study involving 273 inpatients with complicated and uncomplicated skin and soft tissue infections reported a clinical success rate (cure or improvement) of 93.2% at long-term follow up. The most commonly isolated organism was Staphylococcus aureus, although S. epidermidis, S. pyogenes and Enterococcus were also isolated. Patients were treated with either low (250 mg three times a day or 375 mg two times a day) or high doses of Zyvox (375 mg three times a day or 625 mg two times a day). Intravenous therapy was instituted for at least three days before switching to oral treatment.

A second Phase II study in adults who were hospitalized for community-acquired pneumonia caused by S. pneumoniae reported clinical and bacteriological success rates of 94.8% and 96.4%, respectively, at long-term follow up. Other organisms that were isolated included S. aureus, Haemophilis species and group B Streptococcus. Of the 126 patients who were evaluable and had received an average of 9 days of therapy, 73 were microbiologically evaluable. Patients were treated with either the low or high dose regimens described above. Intravenous therapy was instituted for at least three days before changing to oral treatment. Zyvox was well tolerated, the most commonly reported adverse effects being headache, nausea, and diarrhea of generally mild to moderate intensity.

Zyvox (linezolid) is rapidly and completely absorbed after oral dosing and there is no need for dose adjustment when switching from the intravenous to oral route. There was no significant difference in the efficacy of Zyvox when given with or with out food. It is anticipated that the metabolism of Zyvox will be unaffected by inhibitors or inducers of cytochrome P-450 and that Zyvox will not affect the metabolism of compounds cleared by this enzyme system.

What The Patient Should Know

As with all antibiotics it is important to finish the entire course of therapy, unless instructed by a physician, and to avoid missing doses.

Zyvox (linezolid) can be taken without regard to meals. The most common side effects that have been reported have include headache, nausea, and diarrhea.