Sparfloxacin (Systemic)


VA CLASSIFICATION
Primary: AM402

Commonly used brand name(s): Zagam.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antibacterial (systemic)—

Indications

Accepted

Bronchitis, bacterial exacerbations (treatment)—Sparfloxacin is indicated in the treatment of bacterial exacerbations of bronchitis caused by Chlamydia pneumoniae , Enterobacter cloacae , Haemophilus influenzae , Haemophilus parainfluenzae , Klebsiella pneumoniae , Moraxella catarrhalis , Staphylococcus aureus , or Streptococcus pneumoniae {01}.

Pneumonia, community-acquired (treatment)—Sparfloxacin is indicated in the treatment of community-acquired pneumonia caused by C. pneumoniae , H. influenzae , H. parainfluenzae , M. catarrhalis , Mycoplasma pneumoniae , or S. pneumoniae {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Fluoroquinolone {01}.
Molecular weight—
    392.41 {01}

Mechanism of action/Effect:

Bactericidal; sparfloxacin acts intracellularly by inhibiting DNA gyrase {01}. DNA gyrase is an essential bacterial enzyme that controls DNA topology and assists in DNA replication, repair, deactivation, and transcription {01}.

Absorption:

Well absorbed after oral administration. Bioavailability is approximately 92%. {01}

Distribution:

Widely distributed into body fluids and tissues {01}. Concentrations in lower respiratory tract tissues and fluids are three to six times higher than the corresponding plasma concentrations {01}.

Vol D—Approximately 3.9 liters per kg {01}.

Protein binding:

Moderate (approximately 45%) {01}.

Biotransformation:

Hepatic; metabolized primarily by phase II glucuronidation to form a glucuronide conjugate {01}. Metabolism does not utilize or interfere with the cytochrome P450 enzyme system {01}.

Half-life:

Elimination—Mean, approximately 20 hours (range, 16 to 30 hours) {01}.

Time to peak concentration:

Approximately 4 hours (range, 3 to 6 hours) {01}.

Peak serum concentration:

Approximately 1.3 mcg per mL (mcg/mL) after an initial 400-mg loading dose {01}.

Approximately 1.1 mcg/mL at steady-state after administration of 200 mg every 24 hours {01}.

Elimination:
    Fecal—50% {01}.
    Renal—50% {01}; approximately 10% of an orally administered dose is excreted in the urine unchanged {01}.


In dialysis—
        It is not known whether sparfloxacin is removed by dialysis {01}.



Precautions to Consider

Cross-sensitivity and/or related problems

Patients allergic to one fluoroquinolone or other chemically related quinolone derivatives (e.g., cinoxacin, nalidixic acid) may be allergic to other fluoroquinolones also {01}.

Carcinogenicity

Sparfloxacin was not carcinogenic in mice or rats that were administered 3.5 and 6.2 times, respectively, the maximum human dose (400 mg per day) based on a mg per square meter of body surface area basis (mg/m 2) for 104 weeks {01}. These doses correspond to plasma concentrations approximately equal to (in mice) and 2.2 times greater than (in rats) maximum human plasma concentrations {01}.

Mutagenicity

Sparfloxacin was not mutagenic in Salmonella typhimurium TA98, TA100, TA1535, or TA1537, in Escherichia coli strain WP2 uvrA, or in Chinese hamster lung cells. Sparfloxacin and other fluoroquinolones have been shown to be mutagenic in S. typhimurium strain TA102 and to induce DNA repair in E. coli , possibly due to the inhibition of bacterial DNA gyrase. Sparfloxacin induced chromosomal aberrations in Chinese hamster lung cells in vitro at cytotoxic concentrations; however, no increase in chromosomal aberrations or micronuclei in bone marrow cells was observed after sparfloxacin was administered orally to mice. {01}

Pregnancy/Reproduction
Fertility—
Sparfloxacin had no effect on the fertility or reproductive performance of male or female rats at oral doses up to 15.4 times the maximum recommended human dose (400 mg), on a mg/m 2 basis. {01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. Since sparfloxacin has been shown to cause arthropathy in immature animals, use is recommended in pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. {01}

Reproduction studies performed in rats, rabbits, and monkeys at oral doses 6.2, 4.4, and 2.6 times higher than the maximum recommended human dose, respectively, on a mg/m 2 basis, did not show evidence of teratogenic effects. At these doses, sparfloxacin produced clear evidence of maternal toxicity in rabbits and in monkeys, and slight evidence of maternal toxicity in rats. When administered to pregnant rats at clearly defined maternally toxic doses, sparfloxacin induced a dose-dependent increase in the incidence of ventricular septal defects in fetuses. Among the three species tested, this effect was specific to the rat. {01}

FDA Pregnancy Category C {01}.

Breast-feeding

Sparfloxacin is distributed into breast milk. Because of the potential for serious adverse effects in nursing infants, a decision should be made whether to avoid nursing or to discontinue taking sparfloxacin. {01}

Pediatrics

Safety and efficacy have not been established in patients up to 18 years of age. Fluoroquinolones have been shown to cause arthropathy and osteochondrosis in immature animals of several species. {01}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of sparfloxacin in the elderly. However, elderly patients are more likely to have age-related renal function impairment, which may require adjustment of dosage in patients receiving sparfloxacin. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Unlike other fluoroquinolones, sparfloxacin does not alter the pharmacokinetics of cimetidine, digoxin, probenecid, theophylline or other methylxanthines, or warfarin. {01}
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Amiodarone{01} or
» Astemizole{01} or
» Cisapride{01} or
» Disopyramide{01} or
» Erythromycin{01} or
» Pentamidine{01} or
» Phenothiazines{01} or
» Terfenadine{01} or
» Tricyclic antidepressants{01} or
» Other medications reported to prolong the QTc interval    (concurrent use of sparfloxacin with amiodarone and disopyramide has resulted in torsades de pointes {01}; concurrent use of sparfloxacin with amiodarone, astemizole, cisapride, disopyramide, erythromycin, pentamidine, phenothiazines, terfenadine, tricyclic antidepressants, or any other QTc-prolonging medication reported to cause torsades de pointes is contraindicated {01})


» Antacids, aluminum-, calcium-, and/or magnesium-containing{01} or
» Ferrous sulfate{01} or
» Sucralfate{01} or
Zinc{01}    (antacids, ferrous sulfate, sucralfate, and zinc may reduce absorption of sparfloxacin by chelation, resulting in lower serum and urine concentrations {01}; therefore, concurrent use is not recommended {01}; it is recommended that sparfloxacin be taken at least 4 hours after any of these medications {01})




Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Mycobacterium tuberculosis culture{01}    (sparfloxacin may produce a false-negative culture result for M. tuberculosis by suppressing mycobacterial growth {01})

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]){01} and
Alkaline phosphatase{01} and
Aspartate aminotransferase (AST [SGOT]){01}    (serum values may be increased {01})


White blood cells{01}    (count may be increased {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Photosensitivity, history of{01}    (moderate to severe phototoxic reactions have occurred in patients exposed to direct or indirect sunlight or to artificial ultraviolet light during or following sparfloxacin treatment {01}; these reactions also have occurred in patients exposed to shaded or diffuse light, including exposure through glass or during cloudy weather {01}; sparfloxacin should not be used in patients with a history of photosensitivity or whose lifestyle or employment will not permit compliance with the required safety precautions {01})


» Previous allergic reaction to fluoroquinolones or other chemically related quinolone derivatives{01}
» QTc prolongation{01}    (sparfloxacin has been found to increase the QTc interval, predisposing patients with QTc prolongation to the development of torsades de pointes {01})


Risk-benefit should be considered when the following medical problems exist
» Cardiovascular conditions predisposing the patient to proarrhythmic conditions{01}    (sparfloxacin is not recommended in patients with cardiovascular conditions predisposing the patient to proarrhythmic conditions, such as hypokalemia, significant bradycardia, congestive heart failure, myocardial ischemia, and atrial fibrillation {01})


Central nervous system (CNS) disorders, including cerebral arteriosclerosis or epilepsy{01}    (sparfloxacin may cause CNS stimulation or toxicity, increasing the risk of seizures in patients with these conditions {01})


» Renal function impairment{01}    (sparfloxacin is excreted renally {01}; it is recommended that patients with a creatinine clearance of less than 50 mL per minute receive a reduced dose of sparfloxacin {01})




Side/Adverse Effects

Note: Sparfloxacin has been found to increase the QTc interval in healthy volunteers. After a single 400-mg loading dose, a mean increase in the QTc interval of 11 milliseconds in 2.9% of subjects was observed; at steady state, the mean increase was 7 milliseconds in 1.9% of subjects. In clinical trials with 1489 patients, the mean prolongation was 10 milliseconds in 2.5% of patients; 0.7% had a QTc interval greater than 500 milliseconds; however, no arrhythmias were observed. The magnitude of this prolongation does not increase with repeated administration, and the QTc interval returns to baseline within 48 hours of the last dose. {01}
Moderate to severe phototoxic reactions have occurred in patients exposed to direct or indirect sunlight, or to artificial ultraviolet light, during or following sparfloxacin treatment; these reactions also have occurred in patients exposed to shaded or diffuse light, including exposure through glass or during cloudy weather. Phototoxic reactions have occurred with and without the use of sunscreens or sunblocks and have occurred after a single dose of sparfloxacin. Some sunscreen products that block UVA spectrum wavelengths (those containing the active ingredients octocrylene or Parsol® 1789) can moderate the phototoxic effects; however, many over-the-counter sunscreens do not provide adequate UVA protection. The overall incidence of phototoxicity was 7.9% in clinical trials, with 4.1% of the reactions defined as mild, 3.3% as moderate, and 0.6% as severe. In rare cases, reactions recurred up to several weeks after stopping sparfloxacin therapy. Patients should discontinue sparfloxacin at the first sign or symptom of phototoxicity. Sparfloxacin should not be used in patients with a history of photosensitivity or whose lifestyle or employment will not permit compliance with the required safety precautions. {01}
There have been reports of ruptures of the tendons in the shoulder or hand, or of the Achilles tendon, requiring surgical repair or resulting in prolonged disability, in patients taking sparfloxacin and other fluoroquinolones. Patients should discontinue sparfloxacin if they experience pain, inflammation, or rupture of a tendon. They should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been excluded. Tendon rupture can occur at any time during or after sparfloxacin therapy. {01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Phototoxicity{01} (blisters; itching; rash; redness; sensation of skin burning; swelling)

Incidence less frequent
    
QTc prolongation{01}

Incidence rare
    
CNS stimulation{01} (acute psychosis; agitation; confusion; hallucinations; tremors)
    
hypersensitivity reactions{01} (skin rash, itching, or redness)
    
pseudomembranous colitis{01} (abdominal or stomach cramps and pain, severe; abdominal tenderness; diarrhea, watery and severe, which may also be bloody; fever)
    
tendinitis or tendon rupture{01} (pain, inflammation, or swelling in calves, shoulders, or hands)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
CNS effects{01} (dizziness; drowsiness; headache; lightheadedness; nervousness; trouble in sleeping)
    
gastrointestinal effects{01} (abdominal or stomach pain or discomfort; diarrhea; nausea; vomiting)
    
taste perversion{01} (changes in sense of taste)
    
vaginal candidiasis{01} (vaginal itching and discharge)



Those indicating possible pseudomembranous colitis and the need for medical attention if they occur after medication is discontinued
    
Abdominal or stomach cramps and pain, severe {01}
    
abdominal tenderness {01}
    
diarrhea, watery and severe, which may also be bloody {01}
    
fever {01}




Overdose
There is no known antidote for sparfloxacin overdose {01}. It is not known whether sparfloxacin is removed by dialysis {01}.

No deaths occurred within a 14-day observation period after administration of up to 5000 mg per kg of body weight (mg/kg) in mice and rats, or up to 600 mg/kg in dogs {01}. Clinical signs observed included inactivity in mice and dogs; diarrhea in mice and rats; and vomiting, salivation, and tremors in dogs {01}.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Monitoring—Electrocardiogram (ECG) monitoring is recommended due to possible QTc prolongation {01}.

Supportive care—The patient should avoid sun exposure for 5 days {01}.


Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sparfloxacin (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to fluoroquinolones or other quinolone derivatives

Pregnancy—Sparfloxacin is recommended for use during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus because sparfloxacin has been shown to cause arthropathy in immature animals





Breast-feeding—Sparfloxacin is distributed into breast milk; caution should be exercised in making the decision whether to breast-feed, since sparfloxacin has been shown to cause arthropathy in immature animals





Use in children—Safety and efficacy have not been established in children up to 18 years of age because sparfloxacin has been shown to cause arthropathy in immature animals

Other medications, especially amiodarone; aluminum-, calcium-, and/or magnesium-containing antacids; astemizole; cisapride; disopyramide; erythromycin; ferrous sulfate; other medications that prolong the QTc interval; pentamidine; phenothiazines; sucralfate; terfenadine; or tricyclic antidepressants
Other medical problems, especially cardiovascular conditions that predispose the patient to proarrhythmic conditions, photosensitivity reactions (history of), QTc prolongation, or renal function impairment

Proper use of this medication
» Sparfloxacin may be taken with food, milk, or caffeine-containing products

Importance of maintaining adequate fluid intake

» Importance of not missing doses, and taking at evenly spaced times

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Checking with physician if no improvement within a few days

» Avoiding concurrent use of antacids, ferrous sulfate, sucralfate, or zinc and sparfloxacin; taking these products at least 4 hours after administration of sparfloxacin

Possible phototoxicity reactions
» Avoiding exposure to direct or indirect sunlight and to artificial ultraviolet light (e.g., sunlamps) during treatment, and for 5 days after therapy

» Discontinuing sparfloxacin at the first sign or symptom of phototoxicity, such as blistering, itching, rash, redness, sensation of skin burning, or swelling

» If phototoxicity has occurred, avoiding further sunlight and artificial light until the phototoxicity reaction has been resolved, or for 5 days, whichever is longer
» Discontinuing sparfloxacin at the first sign of skin rash or other allergic reaction

» Caution when driving or doing anything else requiring alertness because of possible dizziness, drowsiness, or lightheadedness

» Discontinuing sparfloxacin and notifying physician if pain, inflammation, or rupture of a tendon is experienced; resting and refraining from exercise until the diagnosis of tendinitis or tendon rupture has been excluded


Side/adverse effects
Signs of potential side effects, especially phototoxicity, QTc prolongation, CNS stimulation, hypersensitivity reactions, pseudomembranous colitis, and tendinitis or tendon rupture


General Dosing Information

Diet/Nutrition
Sparfloxacin may be taken with food, milk, or caffeine-containing products {01}.

For treatment of adverse effects


For antibiotic-associated pseudomembranous colitis (AAPMC) {01}:
   • Some patients may develop antibiotic-associated pseudomembranous colitis (AAPMC), caused by Clostridium difficile toxin, during or following administration of sparfloxacin. Mild cases may respond to discontinuation of the drug alone. Moderate to severe cases may require fluid, electrolyte, and protein replacement. {01}
   • In cases not responding to the above measures or in more severe cases, oral doses of an antibacterial medication effective against C. difficile should be administered. {01}
   • In addition, antibiotic-associated pseudomembranous colitis may result in severe watery diarrhea, which may occur during therapy or up to several weeks after therapy is discontinued. If diarrhea occurs, administration of antiperistaltic antidiarrheals (e.g., diphenoxylate and atropine combination, loperamide, opiates) is not recommended since they may delay the removal of toxins from the colon, thereby prolonging and/or worsening the condition. {01}



Oral Dosage Forms

SPARFLOXACIN TABLETS

Usual adult dose
Antibacterial
Oral, 400 mg on the first day, then 200 mg every twenty-four hours for a total of ten days of therapy {01}.


Note: The recommended dose for patients with renal function impairment (creatinine clearance less than 50 mL per minute) is 400 mg on the first day, then 200 mg every forty-eight hours for a total of nine days of therapy {01}.


Usual adult prescribing limits
400 mg {01}.

Usual pediatric dose
Appropriate studies on the relationship of age to the effects of sparfloxacin have not been performed in patients up to 18 years of age. Safety and efficacy have not been established. {01}

Strength(s) usually available
U.S.—


200 mg (Rx) [Zagam{01}]

Packaging and storage:
Store below 40 ºC (104 ºF), preferably between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by the manufacturer.

Auxiliary labeling:
   • Continue medicine for full time of treatment.
   • Avoid too much sun or use of sunlamp.



Revised: 08/10/1998



References
  1. Zagam package insert (Rhone-Poulenc Rorer—US), New 11/96, Rec 2/97.
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