"The U.S. Food and Drug Administration today notified Ranbaxy Laboratories, Ltd., that it is prohibited from manufacturing and distributing active pharmaceutical ingredients (APIs) from its facility in Toansa, India, for FDA-regulated drug product"...
(Generic versions may still be available.)
- Patient Information:
Details with Side Effects
MODERATE TO SEVERE PHOTOTOXIC REACTIONS HAVE OCCURRED IN PATIENTS EXPOSED TO DIRECT OR INDIRECT SUNLIGHT OR TO ARTIFICIAL ULTRAVIOLET LIGHT (e.g., SUNLAMPS) DURING OR FOLLOWING TREATMENT. THESE REACTIONS HAVE ALSO OCCURRED IN PATIENTS EXPOSED TO SHADED OR DIFFUSE LIGHT, INCLUDING EXPOSURE THROUGH GLASS OR DURING CLOUDY WEATHER. PATIENTS SHOULD BE ADVISED TO DISCONTINUE SPARFLOXACIN THERAPY AT THE FIRST SIGNS OR SYMPTOMS OF A PHOTOTOXICITY REACTION SUCH AS A SENSATION OF SKIN BURNING, REDNESS, SWELLING, BLISTERS, RASH, ITCHING, OR DERMATITIS.
The overall incidence of drug related phototoxicity in the 1585 patients who received sparfloxacin during clinical trials with recommended dosage was 7.9% (n=126). Phototoxicity ranged from mild 4.1% (n=65) to moderate 3.3% (n=52) to severe 0.6% (n=9), with severe defined as involving at least significant curtailment of normal daily activity. The frequency of phototoxicity reactions characterized by blister formation was 0.8% (n=13) of which 3 were severe. The discontinuation rate due to phototoxicity independent of drug relationship was 1.1% (n=17).
As with some other types of phototoxicity, there is the potential for exacerbation of the reaction on re-exposure to sunlight or artificial ultraviolet light prior to complete recovery from the reaction. In a few cases, recovery from phototoxicity reactions was prolonged for several weeks. In rare cases, reactions have recurred up to several weeks after stopping sparfloxacin therapy.
EXPOSURE TO DIRECT AND INDIRECT SUNLIGHT (EVEN WHEN USING SUNSCREENS OR SUNBLOCKS) SHOULD BE AVOIDED WHILE TAKING SPARFLOXACIN AND FOR FIVE DAYS FOLLOWING THERAPY. SPARFLOXACIN THERAPY SHOULD BE DISCONTINUED IMMEDIATELY AT THE FIRST SIGNS OR SYMPTOMS OF PHOTOTOXICITY.
These phototoxic reactions have occurred with and without the use of sunscreens or sunblocks and have been associated with a single dose of sparfloxacin. However, a study in healthy volunteers has demonstrated that some sunscreen products, specifically those active in blocking UVA spectrum wavelengths (those containing the active ingredients octocrylene or Parsol® 1789), can moderate the photosensitizing effect of sparfloxacin. However, many over-the-counter sunscreens do not provide adequate UVA protection.
Increases in the QTc interval have been observed in healthy volunteers treated with sparfloxacin. After a single loading dose of 400 mg, a mean increase in QTc interval of 11 msec (2.9%) is seen; at steady-state the mean increase is 7 msec (1.9%). The magnitude of the QTc effect does not increase with repeated administration, and the QTc returns to baseline within 48 hours of the last dose. In clinical trials involving 1489 patients with a baseline QTc measurement, the mean prolongation at steady-state was 10 msec (2.5%); 0.7% of patients had a QTc interval greater than 500 msec; however, no arrhythmic effects were seen.
In a covariate analysis, age did not have a statistically significant contribution to the change in QTc recorded in patients taking sparfloxacin. However, in controlled clinical trials, QTc interval prolongation was more frequently reported as an adverse event in patients ≥ 65 years of age than in younger patients. In these clinical trials, QTc interval prolongation was reported more frequently as an adverse event (defined as QTc ≥ 0.440 sec or ≥ 15% change from baseline) in elderly patients treated with sparfloxacin than in elderly patients treated with a comparator drug. During post marketing surveillance, cardiovascular events including torsades de pointes and other arrhythmias were more frequent in the elderly than in younger patients treated with sparfloxacin although a history of underlying cardiac disease in this population was more common. Sparfloxacin is contraindicated in patients with known QTc prolongation (see CONTRAINDICATIONS).
THE SAFETY AND EFFECTIVENESS OF SPARFLOXACIN IN PEDIATRIC PATIENTS, ADOLESCENTS (UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pediatric Use, Pregnancy, and Nursing Mothers subsections.)
Sparfloxacin has been shown to cause arthropathy in immature dogs when given in oral doses of 25 mg/kg/day (approximately 1.9 times the highest human dose on a mg/m² basis) for seven consecutive days. Examination of the weight-bearing joints of the dogs revealed small erosive lesions of the cartilage. Other quinolones also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species.
Convulsions and toxic psychoses have been reported in patients receiving quinolones, including sparfloxacin. Quinolones may also cause increased intracranial pressure and central nervous system stimulation which may lead to tremors, restlessness/agitation, anxiety/nervousness, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, insomnia, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving sparfloxacin, the drug should be discontinued and appropriate measures instituted. As with other quinolones, sparfloxacin should be used with caution in patients with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). Cases of seizure associated with hypoglycemia have been reported. (See PRECAUTIONS: General, Information for Patients, DRUG INTERACTIONS and ADVERSE REACTIONS.)
Serious and occasionally fatal hypersensitivity (including anaphylactoid or anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolones. Some reactions were accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat, or facial edema), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, and/or itching. Only a few patients had a history of previous hypersensitivity reactions. If an allergic reaction to sparfloxacin occurs, the drug should be discontinued immediately. Serious acute hypersensitivity reactions may require immediate treatment with epinephrine, and other resuscitative measures including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, as clinically indicated.
Serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome); vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonitis; interstitial nephritis; acute renal insufficiency or failure; hepatitis; jaundice; acute hepatic necrosis or failure; anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities. The drug should be discontinued immediately at the first appearance of a skin rash or any other sign of hypersensitivity and supportive measures instituted. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.)
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including sparfloxacin, and may range in severity from mild to lifethreatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis.
Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported with sparfloxacin and other quinolones. Sparfloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been confidently excluded. Tendon rupture can occur at any time during or after therapy with sparfloxacin.
Adequate hydration of patients receiving sparfloxacin should be maintained to prevent the formation of a highly concentrated urine.
Administer sparfloxacin with caution in the presence of renal insufficiency. Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of sparfloxacin may be reduced. Adjustment of the dosage regimen is necessary for patients with impaired renal function-creatinine clearance < 50 mL/min. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
Avoid the concomitant prescription of medications known to prolong the QTc interval, e.g., erythromycin, terfenadine, astemizole, cisapride, pentamidine, tricyclic antidepressants, some antipsychotics including phenothiazines. (See CONTRAINDICATIONS.) Sparfloxacin is not recommended for use in patients with pro-arrhythmic conditions (e.g., hypokalemia, significant bradycardia, congestive heart failure, myocardial ischemia, and atrial fibrillation).
Moderate to severe phototoxicity reactions have been observed in patients exposed to direct sunlight while receiving drugs in this class. Excessive exposure to sunlight should be avoided. In clinical trials with sparfloxacin, phototoxicity was observed in approximately 7% of patients. Therapy should be discontinued if phototoxicity (e.g., a skin eruption) occurs.
As with other quinolones, sparfloxacin should be used with caution in any patient with a known or suspected CNS disorder that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy) or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction). (See WARNINGS and DRUG INTERACTIONS.)
Carcinogenesis, Mutagenesis, Impairment of Fertility
Sparfloxacin was not carcinogenic in mice or rats when administered for 104 weeks at daily oral doses 3.5 - 6.2 times greater than the maximum human dose (400 mg), respectively, based upon mg/m². These doses corresponded to plasma concentrations approximately equal to (mice) and 2.2 times greater than (rats) maximum human plasma concentrations.
In a study of repeated exposure (5 days per week for 40 weeks) of hairless albino mice (SKH-1) to a low dose (0.272 Caucasian human minimal erythema dose [MED]) of solar simulated UV radiation, skin tumors were induced with a median onset time of 43 weeks. As expected for this model, the gross appearance of the tumors in this study was consistent with squamous cell carcinoma or its precursors. When sparfloxacin (6.0 or 12.5 mg/kg/day) was administered by the oral route, the
median tumor onset time was reduced to 38 and 32 weeks, respectively. This reduction in median onset time was similar to that observed when mice were exposed to a higher dose (0.476 Caucasian human MED) of solar simulated UV radiation alone. At a dose level of 12.5 mg/kg/day, mice had skin sparfloxacin concentrations (± SD) of approximately 1.8 μg/g (± 0.26, N=6). Following a 400 mg dose of sparfloxacin, skin levels measured in human subjects averaged 5.5 μg/g (± 6.5, N=11). A similar effect on the time to the development of skin tumors has been observed in this mouse strain with some other fluoroquinolone antibiotics. The clinical significance of these findings to humans is unknown.
Sparfloxacin was not mutagenic in Salmonella typhimurium TA98, TA100, TA1535, or TA1537, in Escherichia coli strain WP2 uvrA, nor in Chinese hamster lung cells. Sparfloxacin and other quinolones have been shown to be mutagenic in Salmonella typhimurium strain TA102 and to induce DNA repair in Escherichia coli, perhaps due to their inhibitory effect on 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.
When Chinese hamster ovary cells were incubated with sparfloxacin in the presence of solar simulated UV radiation, chromosome aberrations were induced at concentrations of sparfloxacin that were not associated with aberrations in the absence of UV. The low level of UV used in the experiment, approximately 375 mJ/cm², was not, by itself, associated with chromosome aberrations, while the high level of UV used in the experiment, approximately 750 mJ/cm², induced fewer aberrations than sparfloxacin plus low or high dose UV.
Impairment of 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 human dose (400 mg) based upon mg/m² (equivalent to approximately 12 times the maximum human plasma concentration).
Pregnancy Category C:Reproduction studies performed in rats, rabbits, and monkeys at oral doses 6.2, 4.4, and 2.6 times higher than the maximum human dose, respectively, based upon mg/m² (corresponding to plasma concentrations 4.5- and 6.5-fold higher than in humans in the monkey and rat, respectively) did not reveal any evidence of teratogenic effects. At these doses, sparfloxacin was clearly maternally toxic to the rabbit and monkey with evidence of slight maternal toxicity observed in the rat. When administered to pregnant rats at clearly maternally toxic doses ( ≥ 9.3 times the maximum human dose based upon mg/m²), sparfloxacin induced a dose-dependent increase in the incidence of fetuses with ventricular septal defects. Among the three species tested, this effect was specific to the rat. There are, however, no adequate and well-controlled studies in pregnant women. Sparfloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See WARNINGS.)
Sparfloxacin is excreted in human milk. Because of the potential for serious adverse reactions in infants nursing from mothers taking sparfloxacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (See WARNINGS.)
Safety and effectiveness in pediatric patients and adolescents under the age of 18 years have not been established. Quinolones, including sparfloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. (See WARNINGS.)
In controlled clinical trials conducted in the United States and Europe, sparfloxacin tablets have been administered to approximately 458 elderly (∃65 years of age) patients. It is known that the QTc interval increases with increasing age. In a covariate analysis, age did not have a statistically significant contribution to the change in QTc recorded in patients taking sparfloxacin. However, in controlled clinical trials, QTc interval prolongation was more frequently reported as an adverse event in patients ∃65 years of age than in younger patients. In addition, QTc interval prolongation was reported more frequently as an adverse event (defined as QTc ∃0.440 sec or ∃15% change from baseline) in sparfloxacin treated elderly patients (7/314) than elderly patients treated with a comparator drug (0/301). Finally, the majority of patients with postmarketing cardiovascular events were elderly; however, it is not possible to exclude the roles of other contributing factors such as underlying cardiovascular diseases and concomitant medications. There were no other apparent overall differences in safety and efficacy observed between the elderly and younger individuals in controlled clinical trials. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Sparfloxacin is known to be excreted renally and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRATION and WARNINGS.)
The pharmacokinetic parameters of sparfloxacin in the elderly were consistent with those observed in normal healthy subjects. (See CLINICAL PHARMACOLOGY : Special Populations.)
Last reviewed on RxList: 4/7/2009
This monograph has been modified to include the generic and brand name in many instances.
Additional Zagam Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.