Qurex® XL is indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions and patient populations listed below.
Complicated Urinary Tract Infections, and Acute Uncomplicated Pyelonephritis
Qurex® XL is indicated for the treatment of complicated urinary tract infections (cUTI) caused by:
Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, Proteus mirabilis, or Pseudomonas aeruginosa and acute uncomplicated pyelonephritis (AUP) caused by Escherichia coli.
Limitations of Use
• The safety and efficacy of ciprofloxacin in treating infections other than urinary tract infections has not been demonstrated.
• Qurex® XL is not indicated for pediatric patients.
Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ciprofloxacin and other antibacterial drugs, Qurex® XL should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with ciprofloxacin may be initiated before results of these tests are known; once results become available appropriate therapy should be continued.
As with other drugs, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.

Dosage
Qurex® XL and ciprofloxacin immediate-release tablets are not interchangeable.
Qurex® XL should be administered orally once daily.

Dosage Guidelines Indication	Dose	Frequency	Usual Duration
Complicated Urinary Tract Infection and Acute Uncomplicated Pyelonephritis	1000 mg	every 24 hours	7–14 Days

Patients whose therapy is started with ciprofloxacin IV for UTIs may be switched to ciprofloxacin extended release tablets when clinically indicated at the discretion of the physician.
Administration
Qurex® XL tablets should be taken whole and not split, crushed, or chewed.
Qurex® XL should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate), as well as sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, metal cations such as iron, and multivitamin preparations with zinc.
Concomitant administration of Qurex® XL with dairy products (like milk or yogurt) or with calcium-fortified products alone should be avoided since decreased absorption is possible. A 2-hour window between substantial calcium intake (greater than 800 mg) and dosing with Qurex® XL is recommended
Adequate hydration of patients receiving Qurex® XL should be maintained to prevent the formation of highly concentrated urine. Crystalluria has been reported with quinolones.
Impaired Renal Function
• In patients with cUTI and acute uncomplicated pyelonephritis with a creatinine clearance of ≤ 30 mL/min, the dose of ciprofloxacin should be reduced from 1000 mg to 500 mg daily. The use of Ciprofloxacin 1000 mg tablets is not recommended in this patient population.
• For patients on hemodialysis or peritoneal dialysis, administer ciprofloxacin after the dialysis procedure is completed (maximum dose should be Ciprofloxacin 500 mg extended release every 24 hours). The use of Ciprofloxacin 1000 mg is not recommended in this patient population.
• For patients on continuous ambulatory peritoneal dialysis (CAPD), the maximum dose should be 500 mg every 24 hours.

 

Hypersensitivity Qurex® XL is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antibacterials, or any of the product components. Tizanidine Concomitant administration with tizanidine is contraindicated

Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects
Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting ciprofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions.
Discontinue Qurex® XL immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including ciprofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.
Tendinitis and Tendon Rupture
Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and also been reported in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis and tendon rupture can occur within hours or days of starting ciprofloxacin, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.
The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors.
Discontinue Qurex® XL immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including ciprofloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.
Peripheral Neuropathy
Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of peripheral neuropathy. Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including
ciprofloxacin. Symptoms may occur soon after initiation of ciprofloxacin and may be irreversible in some patients.
Discontinue Qurex® XL immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including ciprofloxacin, in patients who have previously experienced peripheral neuropathy.
Central Nervous System Effects
Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of central nervous system (CNS) effects, including convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis. Ciprofloxacin may also cause central nervous system (CNS) events including: nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and psychotic reactions that have progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed suicide. These reactions may occur following the first dose. Advise patients receiving ciprofloxacin to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. As with all fluoroquinolones, use Ciprofloxacin with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (for example., certain drug therapy, renal dysfunction). Use Ciprofloxacin when the benefits of treatment exceed the risks, since these patients are endangered because of possible undesirable CNS side effects. Cases of status epilepticus have been reported. If seizures occur, discontinue Ciprofloxacin.
Exacerbation of Myasthenia Gravis
Fluoroquinolones, including Ciprofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid Ciprofloxacin in patients with known history of myasthenia gravis.
Other Serious and Sometimes Fatal Adverse Reactions
Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported in patients receiving therapy with quinolones, including ciprofloxacin. 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 (for example, 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.
Discontinue Qurex® XL immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted.
Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including ciprofloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, including intubation, as indicated.
Hepatotoxicity
Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, have been reported with ciprofloxacin. Acute liver injury is rapid in onset (range 1–39 days), and is often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic or mixed. Most patients with fatal outcomes were older than 55 years old. In the event of any signs and symptoms of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), discontinue treatment immediately.
There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin.
Serious Adverse Reactions with Concomitant Theophylline Use
Serious and fatal reactions have been reported in patients receiving concurrent administration of ciprofloxacin and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Instances of nausea, vomiting, tremor, irritability, or palpitation have also occurred.
Although similar serious adverse reactions have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate.
Clostridium difficile-Associated Diarrhea
Clostridium difficile (C. difficile)-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ciprofloxacin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.
Prolongation of the QT Interval
Some fluoroquinolones, including Ciprofloxacin have been associated with prolongation of the QT interval on the electrocardiogram and cases of arrhythmia. Cases of torsade de pointes have been reported during postmarketing surveillance in patients receiving fluoroquinolones, including Ciprofloxacin.
Avoid Ciprofloxacin in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsade de pointes (for example, congenital long QT syndrome, uncorrected electrolyte imbalance, such as hypokalemia or hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class III antiarrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics. Elderly patients may also be more susceptible to drug-associated effects on the QT interval.
Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals
An increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues, has been observed.
In pre-clinical studies, oral administration of Ciprofloxacin caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species.
Photosensitivity/Phototoxicity
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones including Ciprofloxacin after sun or UV light exposure. Therefore,
avoid excessive exposure to these sources of light. Discontinue Ciprofloxacin if phototoxicity occurs.
Development of Drug Resistant Bacteria
Prescribing Ciprofloxacin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
Potential Risks with Concomitant Use of Drugs Metabolized by Cytochrome P450 1A2 Enzymes
Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Co-administration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the co- administered drug and could lead to clinically significant pharmacodynamic adverse reactions of the co-administered drugs.
Interference with Timely Diagnosis of Syphilis
Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. Perform a serologic test for syphilis in all patients with gonorrhea at the time of diagnosis. Perform follow-up serologic test for syphilis three months after ciprofloxacin treatment.
Crystalluria
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline. Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Avoid alkalinity of the urine in patients receiving ciprofloxacin. Hydrate patients well to prevent the formation of highly concentrated urine.
Pediatric Use
Safety and effectiveness of ciprofloxacin in pediatric patients and adolescents less than 18 years of age have not been established. Ciprofloxacin causes arthropathy in juvenile animals. Ciprofloxacin is not indicated for pediatric patients.
Geriatric Use
Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as ciprofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing ciprofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue ciprofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur.
In a large, prospective, randomized ciprofloxacin clinical trial in cUTI, 49% (509/1035) of the patients were 65 and over, while 30% (308/1035) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients.
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using ciprofloxacin with concomitant drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes.
Renal Impairment
Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternate pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. No dosage adjustment is required for patients with uncomplicated UTIs receiving 500 mg Ciprofloxacin. Dosing in children (less than 18 years of age) with impaired renal function has not been studied.
Hepatic Impairment
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The pharmacokinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been studied.

Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of Ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug.
Drugs That are Affected by and Affecting ciprofloxacin

Drugs That are Affected by ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine.
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate.
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics).
Zolpidem	Avoid use	Co-administration with ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended.
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin.
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable monitor, for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of ciprofloxacin extended release
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration.	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels considerably lower than desired for concurrent administration of these agents with ciprofloxacin.
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the Teratogen Information System concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1–5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for the less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses.
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times the maximum daily human dose of 1000 mg based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4-and 1.3-times the highest recommended therapeutic dose based upon body surface area) produced gastrointestinal toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon body surface area), no maternal toxicity was produced in the rabbit, and no embryotoxicity or teratogenicity was observed.
Nursing Mothers
Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential risk of serious adverse reactions (including articular damage) in infants nursing from mothers taking Ciprofloxacin, 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.

Fluoroquinolones including ciprofloxacin may result in an impairment of the patient's ability to drive or operate machinery due to CNS reactions. This applies particularly in combination with alcohol.

Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical trials in patients with urinary tract infections enrolled 961 patients treated with 500 mg or 1000 mg ciprofloxacin extended release tablets. The overall incidence, type and distribution of adverse reactions were similar in patients receiving both 500 mg and 1000 mg of ciprofloxacin. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
In the clinical trial of cUTI and acute uncomplicated pyelonephritis (AUP) defined as infections occurring in premenopausal, non-pregnant women with no known urological abnormalities or comorbidities, ciprofloxacin extended release tablets (1000 mg once daily) in 517 patients was compared to ciprofloxacin immediate-release tablets (500 mg twice daily) in 518 patients for 7 to 14 days. Discontinuations due to adverse reactions thought to be drug-related occurred in 3.1% (16/517) of patients in the ciprofloxacin arm
and in 2.3% (12/518) of patients in the control arm. The most common reasons for discontinuation in the ciprofloxacin arm were nausea/vomiting (4 patients) and dizziness (3 patients). In the control arm the most common reason for discontinuation was nausea/vomiting (3 patients).
In these clinical trials, the following events occurred in ≥ 2% of all ciprofloxacin patients: nausea (4%), headache (3%), dizziness (2%), diarrhea (2%), vomiting (2%) and vaginal moniliasis (2%).
Adverse reactions, judged by investigators to be at least possibly drug-related, occurring in greater than or equal to 1% of all ciprofloxacin treated patients were: nausea (3%), diarrhea (2%), headache (1%), dyspepsia (1%), dizziness (1%), and vaginal moniliasis (1%). Vomiting (1%) occurred in the 1000 mg group.
Medically important adverse reactions that occurred <1% in ciprofloxacin treated patients:

System Organ Class	Adverse Reactions
Body as a Whole	Abdominal pain, Asthenia, Malaise
Cardiovascular	Bradycardia, Migraine, Syncope
Central Nervous System	Abnormal dreams, Convulsive seizures (including status epilepticus), Depersonalization, Depression (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts and attempted or completed suicide), Hypertonia, Incoordination, Insomnia, Somnolence, Tremor, Vertigo
Gastrointestinal	Constipation, Dry mouth, Flatulence, Thirst
Hepatobiliary Disorders	Liver function tests abnormal
Investigations	Prothrombin decrease
Metabolic	Hyperglycemia, Hypoglycemia
Psychiatric Disorders	Anorexia
Skin/Hypersensitivity	Dry skin, Maculopapular rash, Photosensitivity/phototoxicity reactions, Pruritus, Rash, Skin disorder, Urticarial, Vesiculobullous rash
Special Senses	Diplopia, Taste perversion
Urogenital	Dysmenorrhea, Hematuria, Kidney function abnormal, Vaginitis

Postmarketing Experience
The following adverse reactions have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Postmarketing Reports of Adverse Drug Reactions System Organ Class	Adverse Reactions
Cardiovascular	QT prolongation, Torsade de Pointes, Vasculitis and ventricular arrhythmia
Central Nervous System	Hypertonia, Myasthenia, Exacerbation of myasthenia gravis, Peripheral neuropathy, Polyneuropathy, Twitching.
Eye Disorders	Nystagmus
Gastrointestinal	Pseudomembranous colitis
Hemic/Lymphatic	Pancytopenia (life threatening or fatal outcome), Methemoglobinemia
Hepatobiliary	Hepatic failure (including fatal cases)
Infections and Infestations	Candidiasis (oral, gastrointestinal, vaginal)
Investigations	Prothrombin time prolongation or decrease Cholesterol elevation (serum) Potassium elevation (serum)
Musculoskeletal	Myalgia, Myoclonus, Tendinitis, Tendon rupture
Psychiatric Disorders	Agitation, Confusion, Delirium, Psychosis (toxic)
Skin/Hypersensitivity	Acute generalized exanthematous pustulosis (AGEP) Fixed eruption Serum sickness-like reaction
Special Senses	Anosmia, Hyperesthesia, Hypesthesia, Taste loss.

Adverse Laboratory Changes
Changes in laboratory parameters while on ciprofloxacin are listed below:
Hepatic–Elevations of ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH, serum bilirubin. Hematologic–Eosinophilia, leukopenia, decreased blood platelets, elevated blood platelets, pancytopenia. Renal–Elevations of serum creatinine, BUN, crystalluria, cylindruria, and hematuria have been reported. Other changes occurring were: elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, and leukocytosis.
To report any side effects in KSA:
o National Pharmacovigilance and Drug Safety Centre (NPC)
− Fax: + 966 112057662
− Call NPC at + 966 112038222, Exts: 2317-2356-2353-2354-2334-2340
− Toll free phone: 8002490000
− E-mail: npc.drug@sfda.gov.sa
− Website: www.sfda.gov.sa/npc

 

In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Empty the stomach by inducing vomiting or by gastric lavage. Observe the patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria and administration of magnesium, aluminum or calcium containing antacids, which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (less than 10%) is removed from the body after hemodialysis or peritoneal dialysis.

Mechanism of Action
Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents, ATC code: J01MA02.
Qurex® XL (ciprofloxacin hydrochloride and ciprofloxacin extended release tablets) contain ciprofloxacin, a synthetic broad-spectrum antimicrobial agent for oral administration.
Qurex® XL tablets consist of an immediate release layer and an erosion matrix type controlled-release layer. The tablets contain a combination of two types of ciprofloxacin drug substance, ciprofloxacin hydrochloride and ciprofloxacin (base).
Microbiology
Mechanism of Action
The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.
Mechanism of Resistance
The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of other antimicrobial agents such as beta-lactams, macrolides, tetracyclines, or aminoglycosides; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or drug efflux. In
vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between
< 10-9 to 1x10-6 .
Cross Resistance
There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.
Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections ciprofloxacin.
Gram-positive bacteria
Enterococcus faecalis Staphylococcus saprophyticus
Gram-negative bacteria
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ciprofloxacin (<1 mcg/mL). However, the efficacy of ciprofloxacin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Gram-negative bacteria
Citrobacter koseri
Citrobacter freundii
Edwardsiella tarda
Enterobacter aerogenes
Enterobacter cloacae
Klebsiella oxytoca
Morganella morganii
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Serratia marcescens
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar).1,3 The MIC values should be interpreted according to criteria provided in the following table.
Diffusion Techniques
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3 This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in the following table:

Susceptibility Test Interpretive Criteria for Ciprofloxacin Bacteria	MIC (mcg/mL)			Zone Diameter (mm)
	S	I	R	S	I	R
Enterobacteriaceae	≤1	2	≥4	≥21	16–20	≤15
Enterococcus faecalis	≤1	2	≥4	≥21	16–20	≤15
Pseudomonas aeruginosa	≤1	2	≥4	≥21	16–20	≤15
Staphylococcus saprophyticus	≤1	2	≥4	≥21	16–20	≤15
S=Susceptible, I=Intermediate, R=Resistant.

A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1, 2 Standard ciprofloxacin powder should provide the following range of MIC values noted in following table. For the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in the following table should be achieved.
Acceptable Quality Control Ranges for Ciprofloxacin 

Bacteria	MIC range (mcg/mL)	Zone Diameter (mm)
Enterococcus faecalis ATCC 29212	0.25–2	-
Escherichia coli ATCC 25922	0.004–0.015	30–40
Pseudomonas aeruginosa ATCC 27853	0.25–1	25–33
Staphylococcus aureus ATCC 29213	0.12–0.5	-
Staphylococcus aureus ATCC 25923	-	22–30

 

Absorption
Ciprofloxacin extended release tablets are formulated to release drug at a slower rate compared to immediate-release tablets. Approximately 35% of the dose is contained within an immediate-release component, while the remaining 65% is contained in a slow-release matrix.
Maximum plasma ciprofloxacin concentrations are attained between 1 and 4 hours after dosing with Ciprofloxacin extended release tablets. In comparison to the 250 mg and 500 mg ciprofloxacin immediate-release twice a day (BID) treatment, the Cmax of Ciprofloxacin extended release tablets 500 mg and 1000 mg once daily are higher than the corresponding BID doses, while the AUCs over 24 hours are equivalent.
The following table compares the pharmacokinetic parameters obtained at steady state for these four treatment regimens (500 mg once a day (QD) Ciprofloxacin extended release tablets versus 250 mg BID ciprofloxacin immediate-release tablets and 1000 mg QD Ciprofloxacin extended release tablets versus 500 mg BID ciprofloxacin immediate-release).
Ciprofloxacin Pharmacokinetics (Mean ± SD) Following Ciprofloxacin and Ciprofloxacin extended release Administration

		Cmax (mg/L)		AUC0–24h (mg•h/L)		T1/2 (hr)		Tmax (hr) 1
Ciprofloxacin extended release 500 mg QD Ciprofloxacin 250 mg BID	1.59 ± 0.43 1.14 ± 0.23		7.97 ± 1.87 8.25 ± 2.15		6.6 ± 1.4 4.8 ± 0.6		1.5 (1 – 2.5) 1 (0.5 – 2.5)
Ciprofloxacin extended release 1000 mg QD Ciprofloxacin 500 mg BID	3.11 ± 1.08 2.06 ± 0.41		16.83 ± 5.65 17.04 ± 4.79		6.31 ± 0.72 5.66 ± 0.89		2 (1 – 4) 2 (0.5 – 3.5)

Results of the pharmacokinetic studies demonstrate that Ciprofloxacin extended release may be administered with or without food (for example, high-fat and low-fat meals or under fasted conditions).
Distribution
The volume of distribution calculated for intravenous ciprofloxacin is approximately 2.1–2.7 L/kg. Studies with the oral and intravenous forms of ciprofloxacin have demonstrated penetration of ciprofloxacin into a variety of tissues. The binding of ciprofloxacin to serum proteins is 20% to 40%, which is not likely to be high enough to cause significant protein binding interactions with other drugs. Following administration of a single dose of Ciprofloxacin extended release, ciprofloxacin concentrations in urine collected up to 4 hours after dosing averaged over 300 mg/L for both the 500 mg and 1000 mg tablets; in urine excreted from 12 to 24 hours after dosing, ciprofloxacin concentration averaged 27 mg/L for the 500 mg tablet, and 58 mg/L for the 1000 mg tablet.
Metabolism
Four metabolites of ciprofloxacin were identified in human urine. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. The primary metabolites are oxociprofloxacin (M3) and sulfociprofloxacin (M2), each accounting for roughly 3% to 8% of the total dose. Other minor metabolites are desethylene ciprofloxacin (M1), and formylciprofloxacin (M4). The relative proportion of drug and metabolite in serum corresponds to the composition found in urine. Excretion of these metabolites was essentially complete by 24 hours after dosing. Ciprofloxacin is an inhibitor of CYP1A2 mediated metabolism. Co-administration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug.
Elimination
The elimination kinetics of ciprofloxacin are similar for the immediate-release and the extended release tablet. In studies comparing the ciprofloxacin extended release and immediate-release ciprofloxacin, approximately 35% of an orally administered dose was excreted in the urine as unchanged drug for both formulations. The urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Co-administration of probenecid with immediate-release ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation. Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after oral dosing with the immediate-release tablet, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites. Approximately 20 to 35% of an oral dose of immediate-
release ciprofloxacin is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.
Specific Populations
Elderly
Pharmacokinetic studies of the immediate-release oral tablet (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65 years) as compared to young adults. Cmax is increased16 to 40%, and mean AUC is increased approximately 30%, which can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant.
Renal Impairment
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. No dose adjustment is required for patients with uncomplicated UTIs receiving 500 mg ciprofloxacin extended release tablets. For cUTI and AUP, where 1000 mg is the appropriate dose, the dosage of ciprofloxacin extended release tablets should be reduced to ciprofloxacin extended release tablets 500 mg q24h in patients with creatinine clearance equal to or below 30 mL/min.
Hepatic Impairment
In preliminary studies in patients with stable chronic cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated.
Drug-Drug Interactions
Antacids
Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90%.
Histamine H2-receptor antagonists
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.
Metronidazole
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.
Tizanidine
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg twice a day for 3 days). Concomitant administration of tizanidine and ciprofloxacin extended release is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine.
Ropinirole
In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole once daily with 500 mg ciprofloxacin twice-daily, the mean Cmax and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin extended release.
Clozapine
Following concomitant administration of 250 mg ciprofloxacin with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethyl-clozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin extended release are advised.
Sildenafil
Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg ciprofloxacin to healthy subjects, the mean Cmax and mean AUC of sildenafil were both increased approximately two-fold. Use sildenafil with caution when co-administered with ciprofloxacin extended release due to the expected two-fold increase in the exposure of sildenafil upon co-administration of ciprofloxacin.
Duloxetine
In clinical studies, it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold increase in mean Cmax of duloxetine.
Lidocaine
In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg ciprofloxacin twice daily resulted in an increase of lidocaine Cmax and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible interaction with ciprofloxacin extended release and an increase in adverse reactions related to lidocaine may occur upon concomitant administration.
Metoclopramide
Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in a shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin.
Omeprazole
When ciprofloxacin extended release was administered as a single 1000 mg dose concomitantly with omeprazole (40 mg once daily for three days) to 18 healthy volunteers, the mean AUC and Cmax of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined.
 

 

Non-clinical data reveal no special hazards for humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential, or toxicity to reproduction. Like a number of other quinolones, ciprofloxacin is phototoxic in animals at clinically relevant exposure levels. Data on photomutagenicity/photocarcinogenicity show a weak photomutagenic or phototumorigenic effect of ciprofloxacin in-vitro and in animal experiments. This effect was comparable to that of other gyrase inhibitors.
Articular tolerability: As reported for other gyrase inhibitors, ciprofloxacin causes damage to the large weight-bearing joints in immature animals. The extent of the cartilage damage varies according to age, species and dose; the damage can be reduced by taking the weight off the joints. Studies with mature animals (rat, dog) revealed no evidence of cartilage lesions. In a study in young beagle dogs, ciprofloxacin caused severe articular changes at therapeutic doses after two weeks of treatment, which were still observed after 5 months.

Inactive ingredients: Crospovidone, magnesium stearate, colloidal anhydrous silica, succinic acid, hypromellose, titanium dioxide and macrogol.

Not applicable.

24 Months

Do not store above 30°C.

Immediate packaging	Outer packaging
PVC/PVDC Aluminum foil	Carton Leaflet

No special requirements.