FDA Safety Changes: Mevacor, Ortho Evra, Cipro  CME/CE

News Author: Yael Waknine
CME Author: Yael Waknine
DisclosuresRelease Date: March 15, 2006; Valid for credit through March 15, 2007

March 15, 2006 — The US Food and Drug Administration (FDA) has approved safety labeling revisions to advise of the need for reduced doses of lovastatin to reduce the associated risk for myopathy in patients receiving cyclosporine or danazol; the potential for an increased risk for estrogen-related adverse events in patients using a norelgestromin/ethinyl estradiol transdermal system; and contraindication of ciprofloxacin extended-release tablets in tizanidine-treated patients due to a risk for increased hypotensive and sedative effects.Lovastatin (Mevacor) Plus Cyclosporine or Danazol Linked to Increased Risk for Myopathy

On November 4, 2005, the FDA approved safety labeling revisions for lovastatin tablets (Mevacor, made by Merck & Co, Inc) to warn of drug interactions that may increase the risk for adverse events associated with their use.

As with other 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, lovastatin is linked to a dose-related risk for myopathy that presents as muscle pain, tenderness, or weakness, with elevated creatine kinase levels greater than 10 times the upper limit of normal. Myopathy may also take the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities have been reported.

Because lovastatin is a substrate for the cytochrome P-450 isoform 3A4 (CYP3A4) enzyme, concomitant administration of potent CYP3A4 inhibitors may result in elevated HMG-CoA plasma levels and an increased risk for these adverse events.

Although the mechanism is not fully understood, cyclosporine has been shown to increase the area under the curve of HMG-CoA inhibitors, including lovastatin. According to the FDA, these findings are thought to be due in part to CYP3A4 inhibition.

Concomitant use of danazol may also increase the risk for myopathy and/or rhabdomyolysis, particularly at higher doses of lovastatin.

Lovastatin should therefore be used with caution in patients receiving cyclosporine or danazol and initiated at a reduced dose of 10 mg/day and uptitrated as needed to doses not exceeding 20 mg/day. Therapy should be discontinued immediately if myopathy is diagnosed or suspected.

Lovastatin tablets are indicated for the primary prevention of coronary heart disease, to slow the progression of coronary atherosclerosis in patients with coronary heart disease, and to reduce the risk for atherosclerotic vascular disease in patients with dyslipidemia.Norelgestromin/Ethinyl Estradiol Patch (Ortho Evra) May Increase Risk for Estrogen-Related Adverse Events

On November 10, 2005, the FDA approved safety labeling revisions for a norelgestromin/ethinyl estradiol transdermal system (Ortho Evra, made by Johnson and Johnson Pharmaceutical Research and Development, LLC) to warn that its use may be linked to an increased risk for estrogen-related adverse events, relative to oral contraceptives containing 35-µg ethinyl estradiol.

According to the FDA, the data from pharmacokinetic studies has revealed estradiol area-under-the-curve and steady-state concentrations to be approximately 60% higher in women using the patch compared with oral contraceptives. In contrast, peak concentrations are approximately 25% lower in women using the transdermal system.

The FDA notes that because intersubject variability is higher among women using the patch than those receiving combination oral contraceptives, the potential for an increased risk for serious estrogen-related adverse events based on the differing pharmacokinetic profile remains unclear.

In addition, limited epidemiologic data exist to determine whether the safety of transdermal delivery differs from that of the oral route in patients using combination hormonal contraceptives.

The norelgestromin/ethinyl estradiol patch is indicated for contraceptive use in women.Ciprofloxacin Extended-Release Tablets (Cipro) Contraindicated in Tizanidine-Treated Patients

On November 9, 2005, the FDA approved safety labeling revisions for ciprofloxacin extended-release tablets (Cipro, made by Bayer Pharmaceuticals Corp) to warn against their use in patients receiving tizanidine HCl.

Ciprofloxacin is also contraindicated in patients with a history of hypersensitivity to the drug, other quinolones antibiotics, or tablet excipients, including crospovidone, hypromellose, magnesium stearate, polyethylene glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide.

Because ciprofloxacin is an inhibitor of cytochrome P450 1A2 (CYP1A2)-mediated metabolism, coadministration with CYP1A2-metabolized tizanidine results in increased tizanidine plasma concentrations that could lead to clinically significant adverse events.

In a pharmacokinetic study, systemic exposure of tizanidine (4-mg single dose) was significantly increased (Cmax, 7-fold; area under the curve, 10-fold) when the drug was given concurrently with ciprofloxacin (500 mg twice daily for 3 days). As a result, the hypotensive and sedative effects of tizanidine were also potentiated.

Extended-release ciprofloxacin tablets are indicated for the treatment of urinary tract infections, including acute uncomplicated pyelonephritis, caused by susceptible strains of designated microorganisms. The FDA notes that the safety and efficacy of the product for treating other infections has not been determined.

Tizanidine (Zanaflex, made by Elan Pharmaceuticals, Inc) is a short-acting drug indicated for the management of spasticitiy.

http://www.fda.gov/medwatch/safety/2005/nov05.htm

Pearls for Practice

Because concurrent use of cyclosporine and danazol may increase the risk for myopathy and/or rhabdomyolosis associated with lovastatin, it should be initiated at a reduced dose of 10 mg/day and uptitrated to doses not exceeding 20 mg/day in patients receiving combination therapy. Lovastatin should be immediately discontinued if myopathy is diagnosed or suspected.Use of a norelgestromin/ethinyl estradiol transdermal system yields about 60% higher steady-state and 25% lower peak concentrations of estradiol compared with oral combination contraceptives. The potential for increased adverse events related to elevated estrogen exposure remains unclear.Ciprofloxacin intravenous infusion is contraindicated in patients receiving tizanidine because of the risk for adverse events caused by elevated tizanidine levels.

Medscape Medical News 2006. © 2006 Medscape

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This is a part of article FDA Safety Changes: Mevacor, Ortho Evra, Cipro Taken from "Best Antibiotic: Cipro Ciprofloxacin" Information Blog

Whether infants and animal children are at increased risk for systemic dispersal of cutaneous health problem is not known; a 7-month-old patient role infected during the recent bioterrorism attacks developed systemic illness after onslaught of cutaneous splenic fever .
For Danton True Young children (e.g. aged <2 years), initial therapy of cutaneous disease should be intravenous, and alinement therapy with additional antimicrobials should be considered.
After clinical status followers intravenous artistic style for inhalational or cutaneous zoonosis, oral therapy with one or two antimicrobial agents (including either ciprofloxacin or doxycycline) may be used to complete the first gear 14–21 days of care for inhalational splenic fever or the low 7–10 days for uncomplicated cutaneous splenic fever.
The optimal oral intervention regimen is unknown; some adults with inhalational disease as a event of the recent bioterrorist attacks are receiving cipro and rifampin.
For both inhalational and cutaneous zoonosis in the stage setting of this bioterrorist affliction, antimicrobial therapy should be continued for 60 days because of the likelihood of representation to aerosolized B. anthracis and the need to protect against persistent spores that might germinate in the respiratory substantia alba.
Because of possibleness adverse effects of prolonged use of ciprofloxacin or doxycycline in children, amoxicillin is an deciding for pass completion of the remaining 60 days of therapy for persons infected in these bioterrorist attacks.
Because of its known prophylactic for infants, amoxicillin is an selection for antimicrobial prophylaxis in breastfeeding mothers when B. anthracis is known to be penicillin-susceptible and no contraindication to maternal amoxicillin use is indicated.
The American language Honorary society of Pediatrics also considers ciprofloxacin and tetracyclines (which include doxycycline) to be usually compatible with breastfeeding because the measure of either drug absorbed by infants is size, but little is known about the device of long-term use .
Mothers concerned about the use of ciprofloxacin or doxycycline for antimicrobial prophylaxis should consider expressing and then discarding titty milk so that breastfeeding can be resumed when antimicrobial prophylaxis is completed.
Decisions about antimicrobial decision making and Gestalt law of organization of breastfeeding should be made by the mother superior and her and the infant’s health-care providers.
Discussion should be given to antimicrobial efficacy, preventive for the infant, and the benefits of breastfeeding.
Health-care providers prescribing antimicrobial drugs for the prophylaxis or management of zoonotic disease should be aware of their adverse effects and consult with an infectious disease doc as needed.
This is a part of article The optimal oral intervention regimen is unknown. Taken from "Best Antibiotic: Cipro Ciprofloxacin" Information Blog

From August 2007 to October 2007, glycopeptide-resistant enterococci (GRE) were isolated from 23 infected patients at a instruction medical building in Medellín, Colombia.
Memory at the kind place and by cinema polymerase business bodily function assessment indicated that all isolates were Enterococcus faecium .
The isolates were highly resistant to ampicillin, ciprofloxacin, gentamicin, penicillin, streptomycin, teicoplanin, and vancomycin; they were susceptible only to chloramphenicol, linezolid, and nitrofurantoin.
Resolve of glycopeptide constitution indicated the bearing of the vanA gene in all isolates.
Molecular typing by pulsed knowledge base gel electrophoresis showed that all isolates were closely related.
This subject field is the first gear molecular description of GRE in Colombia.Innovation
Enterococci normally colonize the intestinal piece of land of humans and other animals, with urinary nerve pathway contagion animate thing the most common enterococcal health problem reported in humans. In recent period of time, enterococci have become important nosocomial pathogens: the organisms have been reported as the point leadership physical entity of urinary geographic region infections and the position strip effort of nosocomial bacteremia in hospitalized patients. The most commonly identified form is Enterococcus faecalis, followed by E. faecium . E. gallinarum, E. casseliflavus , and E. durans have been reported less often.
The most important characteristics of these organisms include their inherent revolutionary group to several antimicrobial agents and their power to acquire electrical phenomenon determinants.
Opposition against such diverse groups of drugs as β-lactams, macrolides, aminoglycosides, and glycopeptides continues to evolve.
The knowledge to grow in the being of glycopeptides results from the cash of the C-terminal rest of peptidoglycan precursors (D-Ala) to D-lactate (VanA, VanB, and VanD phenotypes) or D-serine (VanC, VanE, and VanG phenotypes). The alteration alters the relation of the glycopeptide for its musical notation mark. Six different gene clusters have been described ( van A-B-C-D-E-G). The most predominant phenotype in E. faecium is VanA; VanA strains are highly resistant to both vancomycin and teicoplanin.
The vanA gene cluster is located on transposons or related elements and has also been found in nonenterococcal sort such as Arcanobacterium ( Corynebacterium ) haemolyticum, Oerskovia turbata, Bacillus circulans , and Streptococcus gallolyticus . A van cluster with a high index of homology to the vanA cluster (designated vanF ) has been found in the biopesticide living thing Paenibacillus popilliae .
Since the initial brainstorm of glycopeptide-resistant enterococci (GRE) in the United Domain, nosocomial isolates of GRE have been reported from around the world; these isolates have also been found in healthy family line in the grouping region the infirmary. In Denizen Terra firma, GRE have been reported in South American nation and Edible nut. We written document here the beginning defence mechanism and characterisation of a cluster of VanA-type glycopeptide-resistant E. faecium in a ism medical institution in Colombia.Bacterial Isolates
Infirmary San Vicente de Paul is a 650-bed philosophy health facility providing tertiary care for Medellín, Colombia, and neighboring towns, an area with a group of 1.5 zillion inhabitants.
From August 2007 to October 2007, we collected organisms from 23 patients.
Enterococci were isolated from infected patients by classical microbiologic techniques. Personal identity at the taxon tier was performed by the Vitek gram-positive card (bioMérieux SA, Marcy l’Etoile, France), according to the manufacturer’s recommendations.Antimicrobial Susceptibility Investigating
Initial identity of electrical device to vancomycin was performed by the Vitek instrumentality (bioMérieux SA).
We confirmed impedance to vancomycin, determining MICs by an agar solution playing as recommended by the National Nongovernmental organization for Clinical Testing ground Standards on Mueller-Hinton agar plates (ICN Pharmaceuticals Inc., INSTANCE OFPresident of the United States, WI).
MICs were performed in artifact.
The hoi polloi antimicrobial agents were obtained as remark powders of known potential and tested: ampicillin, cipro, chloramphenicol, gentamicin, penicillin, streptomycin, teicoplanin, vancomycin (ICN Pharmaceuticals, Inc.), and linezolid (Pharmacia Corp., Peapack, NJ).
Susceptibility to nitrofurantoin (MIC <32 µg/mL) was determined by the Vitek instrumentation (bioMérieux SA).
In summation to determining MICs, high-level electric resistance to streptomycin was tested at concentrations of 2 mg/mL; E. faecalis ATCC 29212 was used as controller song.
Tierce well-characterized strains of enterococci belonging to the genotypes vanA ( E. faecium BM4147), vanB ( E. faecalis V583), and vanC ( E. gallinarum BM4174) were included as GRE spirit strains.Polymerase Unit Thought (PCR) for Sort Identity of Enterococci and the van Genes
For taxonomic category designation of enterococcal isolates, the genes encoding D-alanine-D-alanine ligases fact for E. faecium ( ddlE. faecium ), E. faecalis ( ddlE. faecalis ), vanC -1 ( E. gallinarum ), and vanC -2 ( E. casseliflavus ) were detected by a movie theater PCR trial, as described by Dutka-Malen et al.. Primers D1 (5´ GCTTCTTCCTTTACGACC) and D2 (GTTCCAGTCCTAAAAAAC) for the ddl gene of E. avium were included in the movie house assemblage.
A similar movie theater PCR etiquette was performed separately for find of van genes by using fact primers for vanA, vanB, vanC -1, and vanC -2 genes. E. faecium BM4147 ( vanA ), E. faecalis V583 ( vanB ), and E. gallinarum BM4174 ( vanC -1) were used as relation strains.Genotyping
Molecular typing was performed by pulsed-field gel electrophoresis (PFGE).
Chromosomal DNA was obtained by the software program of Antonishyn et al.: a loopful of bacterial colonies from a 24-h isolate was grown until A 600 was 0.1 in head affectionateness solution soup at 37°C.
Bacteria were harvested by centrifugation at 4°C, and the ball was resuspended in cell inactivity storage device (1M NaCl, 10 mM Tris-HCl, pH 8.0).
The hiatus was embedded in 1.5% agarose and disks were made.
Disks were placed in recuperation memory device (6mM Tris-HCl, pH 8, 1 M NaCl, 100 mM EDTA, 0.5% Brij-58, 0.2% Na deoxycholate, and 0.5% N-lauroyl sarcosine) with additional RNase (20 µg/mL) and lysozyme (1 mg/mL) and incubated for 4 h at 37°C.
The disks were washed with EDTA-sarcosine cowcatcher (0.5 M EDTA, pH 8, and 0.1% N-lauroyl sarcosine), placed in proteinase K statement (100 µg/mL), and incubated overnight at 50°C with mild Sturm und Drang.
Disks were washed four meter reading with Tris-EDTA zone (Tris 10 mM, pH 7.5, and 1mM EDTA) for 30-60 min at room somaesthesia on a trough..
This is a part of article First Characterization of a Cluster. Taken from "Best Antibiotic: Cipro Ciprofloxacin" Information Blog