Cipro XL 1000 mg

No dosage adjustment based on age alone is necessary for elderly patients. 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. C_max is increased 16% 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.

Since ciprofloxacin is substantially excreted by the kidney, the risk of adverse reactions may be greater in patients with impaired renal function. No significant accumulation of ciprofloxacin is anticipated in elderly subjects with renal impairment who take CIPRO XL 500 mg, therefore, no reductions in dosage are required.

However, in patients with renal impairment where CIPRO XL 1000 mg once daily is the appropriate dose, dosage may need to be reduced to CIPRO XL 500 mg once daily (see Dosage, Impaired Renal Function).

In one study, the apparent volume of distribution (Vd_area) of CIPRO was estimated from kinetic data recorded after oral doses and found to be approximately 3.5 L/kg. Studies with the oral and intravenous forms of ciprofloxacin have demonstrated penetration of ciprofloxacin into a variety of tissues. A single dose study in healthy subjects has demonstrated penetration of ciprofloxacin into prostate tissue following administration of CIPRO XL 1000 mg. One and three hours after dosing, mean ciprofloxacin concentrations were greater than 4 µg/g. 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 CIPRO XL (500 mg or 1000 mg), ciprofloxacin concentrations in urine, collected up to 4 hours after dosing, averaged over 300 mg/L and over 500 mg/L, respectively; in urine excreted from 12 to 24 hours after dosing, ciprofloxacin concentration averaged 27 mg/L for CIPRO XL 500 mg and 58 mg/L for CIPRO XL 1000 mg.

Clinical pharmacology studies have compared the pharmacokinetics of CIPRO XL to CIPRO (ciprofloxacin) (immediate release formulation) (CIPRO XL 500 mg vs. CIPRO 250 mg BID and CIPRO XL 1000 mg vs. CIPRO 500 mg BID, respectively), examined the effects of various meals on the pharmacokinetics of CIPRO XL, and investigated possible drug interactions.

Since the mean peak plasma concentration (C_max) of CIPRO XL 500 mg tablets (1.59 mg/L) does not exceed that of CIPRO 500 mg tablets (2.36 mg/L), the effect of CIPRO XL 500 mg with respect to special populations (elderly, renal impairment, hepatic impairment) (see Special Populations) and drug-drug interactions is expected to be similar to that of CIPRO 500 mg tablets, which has been extensively studied.

Since the CIPRO XL formulation entails only a slight modification of drug release, the overall performance of the CIPRO XL 1000 mg formulation with respect to special populations and drug-drug and drug-disease interactions is expected to be similar to that of CIPRO, which has been extensively studied.

The relative bioavailability of CIPRO XL 1000 mg compared to CIPRO 500 mg tablet BID was examined in a crossover study of 20 healthy male volunteers under fasted conditions. Mean concentrations for Day 1 are shown in Figure 1.

The elimination kinetics of ciprofloxacin are similar for CIPRO XL and CIPRO (immediate release formulation). The mean serum elimination half-life (t_1/2) of CIPRO XL (ciprofloxacin) extended release is 6.6 (± 1.4) hours and 6.3 (± 0.7) hours, for the 500 mg and 1000 mg tablets, respectively. The major route of elimination of ciprofloxacin in humans is as unchanged drug in urine.

Four metabolites of ciprofloxacin were identified in human urine. 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.

In preliminary studies in patients with stable chronic liver cirrhosis (with mild to moderate hepatic impairment), no significant changes in ciprofloxacin pharmacokinetics were observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency and stable chronic cirrhosis (with severe hepatic impairment), however, have not been elucidated.

In a study of 7 cirrhotic patients and healthy volunteers given CIPRO 750 mg every 12 hours for a total of nine doses followed by a 1 week washout and then a 30 minute infusion of CIPRO I.V. 200 mg, there was no difference in pharmacokinetics between patients with stable chronic cirrhosis (with mild to moderate hepatic impairment) and healthy volunteers.

In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Since the total drug exposure attained with CIPRO XL 500 mg does not exceed that achieved with CIPRO 500 mg tablets (immediate release formulation), which is approved as a total daily dose for use in renally impaired patients, no dosage adjustment for renal disease is required with CIPRO XL 500 mg.

For complicated urinary tract infections or acute uncomplicated pyelonephritis, where 1000 mg is the appropriate dose, the dosage of CIPRO XL should be reduced to 500 mg CIPRO XL once daily in patients with creatinine clearance below 30 mL/min (see Dosage, Impaired Renal Function).

Caffeine: Ciprofloxacin has also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.

Clozapine: Following concomitant administration of 250 mg ciprofloxacin for 7 days, serum concentrations of clozapine and n-desmethylclozapine were increased by 29% and 31%, respectively (see Warnings).

Cyclosporine: Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine levels in patients who are concomitantly receiving cyclosporine.

Ferrous Sulfate: Oral ferrous sulfate at therapeutic doses decreases the bioavailability of oral ciprofloxacin, therefore concomitant therapy is not advised.

Food and Dairy Products: Although CIPRO XL may be taken with meals that include milk, simultaneous administration with dairy products alone, or with calcium-fortified products should be avoided, since decreased absorption is possible. It is recommended that CIPRO XL be administered at least 2 hours before or 2 hours after substantial calcium intake (>800 mg) (see Dosage).

Glyburide: In particular cases, concurrent administration of ciprofloxacin and glyburide can intensify the action of glyburide (hypoglycemia).

Histamine H₂-receptor Antagonists: Histamine H₂-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.

Lidocaine: It was demonstrated in healthy subjects that concomitant use of lidocaine with ciprofloxacin, a moderate inhibitor of CYP450 1A2 isozyme, reduces clearance of intravenous lidocaine by 22%. Ciprofloxacin may increase the systemic toxicity of lidocaine.

Methotrexate: Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate-associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant therapy is indicated.

Metoclopramide: Metoclopramide accelerates the absorption of ciprofloxacin (oral) resulting in a shorter time to reach maximum plasma concentrations. No effect was seen on the bioavailability of ciprofloxacin.

Multivalent Cations: Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, polymeric phosphate binders such as sevelamer, sucralfate, Videx (didanosine) chewable/buffered tablets or pediatric powder, mineral supplements or products containing calcium, iron, or zinc may substantially interfere with the absorption of the quinolone, resulting in serum and urine levels considerably lower than desired. CIPRO XL should be administered at least 2 hours before or 6 hours after these preparations. When CIPRO XL, given as a single 1000 mg dose, was administered 2 hours before or 4 hours after a magnesium/aluminum-containing antacid (900 mg aluminum hydroxide and 600 mg magnesium hydroxide as a single oral dose) to 18 healthy volunteers, there was a 4% and 19% reduction, respectively, in the mean C_max of ciprofloxacin. The reduction in the mean AUC was 24% and 26%, respectively (see Dosage).

NSAID: Concomitant administration of a nonsteroidal anti-inflammatory drug (fenbufen) with a quinolone (enoxacin) has been reported to increase the risk of CNS stimulation and convulsive seizures.

Omeprazole: Absorption of the CIPRO XL tablet was slightly diminished (20%) when given concomitantly with omeprazole.

Probenecid: Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomitantly.

Ropinirole: In a clinical study it was shown that concomitant use of ropinirole with ciprofloxacin, a medium inhibitor of the CYP450 1A2 isozyme, resulted in increases in the C_max and AUC of ropinirole of 60 and 84%, respectively. Ciprofloxacin may increase the systemic toxicity of ropinirole.

Theophylline: Concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions (see Adverse Effects). If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

Tizanidine: In a clinical study in healthy subjects there was an increase in tizanidine serum concentrations (C_max increase: 7-fold, range: 4 to 21-fold; AUC increase: 10-fold, range: 6 to 24-fold) when given concomitantly with ciprofloxacin. Associated with the increased serum concentrations was a potentiated hypotensive and sedative effect. Tizanidine must not be administered together with ciprofloxacin (see Contraindications, Warnings).

Warfarin: Quinolones have been reported to enhance the effects of the oral anticoagulant warfarin and its derivatives. During concomitant administration of these drugs, the prothrombin time/INR, or other appropriate coagulation tests, should be closely monitored.

No dosage adjustment based on age alone is necessary for elderly patients. Since ciprofloxacin is substantially excreted by the kidney, the risk of adverse reactions may be greater in patients with impaired renal function. No significant accumulation of ciprofloxacin is anticipated in elderly subjects with renal impairment who take CIPRO XL 500 mg, therefore, no reductions in dosage are required.

However, in patients with renal impairment, where CIPRO XL 1000 mg once daily is the appropriate dose, dosage may need to be reduced to CIPRO XL 500 mg once daily (see Dosage, Impaired Renal Function).

Ciprofloxacin is excreted in human milk. Because of the potential for serious adverse reactions in infants nursing from women taking ciprofloxacin, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the woman and possible risk to the infant (see Warnings).

The safety and efficacy of ciprofloxacin in the pediatric population less than 18 years of age have not been established. Quinolones, including ciprofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species (see Warnings).

Adequate and well-controlled studies have not been performed in pregnant women. Ciprofloxacin should not be used in pregnant women unless the potential benefits outweigh the potential risk to the fetus (see Warnings).

In preliminary studies in patients with stable chronic liver cirrhosis (with mild to moderate hepatic impairment), no significant changes in CIPRO pharmacokinetics were observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency and stable chronic cirrhosis (with severe hepatic impairment), however, have not been elucidated. An increased incidence of nausea, vomiting, headache and diarrhea were observed with the use of CIPRO in this patient population. No dosage adjustment is required with CIPRO XL in patients with stable chronic cirrhosis (with mild to moderate hepatic impairment).

Ability to Drive and Operate Machinery: Even when ciprofloxacin is taken exactly as prescribed, it can affect the speed of reaction to such an extent that the ability to drive or to operate machinery is impaired. This applies particularly in combination with alcohol.

In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Since the total drug exposure attained with CIPRO XL (ciprofloxacin) extended release 500 mg tablets does not exceed that achieved with CIPRO (ciprofloxacin) 500 mg tablets (immediate release formulation), which is approved as a total daily dose for use in renally impaired patients, no dosage adjustment for renal disease is required with CIPRO XL 500 mg.

For complicated urinary tract infections or acute uncomplicated pyelonephritis, where 1000 mg is the appropriate dose, the dosage of CIPRO XL should be reduced to 500 mg CIPRO XL once daily in patients with creatinine clearance below 30 mL/min (see Dosage).

Each nearly white to slightly yellowish, film-coated, oblong-shaped, extended release tablet, coded with the word “BAYER” on one side and “C1000 QD” on the reverse side, contains: ciprofloxacin 1000 mg as ciprofloxacin HCl (574.9 mg, calculated as ciprofloxacin on the dried basis) and ciprofloxacin (425.2 mg, calculated on the dried basis). Nonmedicinal ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene glycol, silical colloidal anhydrous, succinic acid and titanium dioxide. Bottles of 50. Store at 15 to 30°C.

Each nearly white to slightly yellowish, film-coated, oblong-shaped, extended release tablet, coded with the word “BAYER” on one side and “C500 QD” on the reverse side, contains: ciprofloxacin 500 mg as ciprofloxacin HCl (287.5 mg, calculated as ciprofloxacin on the dried basis) and ciprofloxacin (212.6 mg, calculated on the dried basis). Nonmedicinal ingredients: crospovidone, hypromellose, magnesium stearate, polyethylene glycol, silical colloidal anhydrous, succinic acid and titanium dioxide. Bottles of 50. Store at 15 to 30°C.

Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including tremors, restlessness, lightheadedness, confusion and hallucinations, depression, nervousness, agitation, insomnia, anxiety, paranoia, nightmares and, rarely, suicidal thoughts or acts. In rare cases, depression or psychosis can progress to self-endangering behavior. These reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors that predispose to seizures or lower the seizure threshold (see Adverse Effects).

C. difficile-associated disease: C. difficile-associated disease (CDAD) has been reported with the use of many antibacterial agents, including ciprofloxacin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of the colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against C. difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against C. difficile. Drugs that inhibit peristalsis may delay clearance of C. difficile and its toxins, and therefore should not be used in the treatment of CDAD. Surgical evaluation should be instituted as clinically indicated since surgical intervention may be required in certain severe cases. (See Adverse Effects.)

Serious hypersensitivity and/or anaphylactic reactions have been reported in patients receiving quinolone therapy, including ciprofloxacin. These reactions may occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnea, urticaria, itching and other serious skin reactions.

Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.

Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving therapy with all antibiotics. 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, hepatic necrosis with fatal outcome, anemia including hemolytic and aplastic, thrombocytopenia including thrombotic thrombocytopenic purpura, leukopenia, agranulocytosis, pancytopenia, and/or other hematologic abnormalities (see Contraindications and Precautions, Drug Interactions).

Ciprofloxacin is known to be a moderate inhibitor of the CYP450 1A2 enzymes. Care should be taken when other drugs are administered concomitantly which are metabolized via the same enzymatic pathway (e.g., theophylline, methylxanthines, caffeine, duloxetine, clozapine). Increased plasma concentrations associated with drug specific side effects may be observed due to inhibition of their metabolic clearance by ciprofloxacin (see Contraindications and Precautions, Drug Interactions).

dry skin, maculopapular rash, pruritus, rash, skin disorder, urticaria, vesiculobullous rash.

prothrombin/INR decreased.

abdominal pain, anorexia, dry mouth, dyspepsia, dysphagia, enlarged abdomen, flatulence, gastrointestinal moniliasis, jaundice, stomatitis, vomiting, abnormal liver function test. The following have been reported rarely (>0.01%-<0.1%): moniliasis (oral), cholestatic jaundice, pseudomembranous colitis. The following have been reported very rarely: constipation, esophagitis, gastrointestinal hemorrhage, glossitis, hepatomegaly, ileus, increased appetite, intestinal perforation, life-threatening pseudomembranous colitis with possible fatal outcome, liver damage, melena, pancreatitis, tenesmus, tooth discoloration, toxic megacolon, ulcerative stomatitis.

abnormal vision (visual disturbances), taste perversion, tinnitus. The following have been reported rarely: transitory deafness (especially at higher frequencies), taste loss (impaired taste). The following have been reported very rarely: chromatopsia, colour blindness, conjunctivitis, corneal opacity, diplopia, ear pain, eye pain, parosmia (impaired smell), anosmia (usually reversible on discontinuation).

pruritus, rash, maculopapular rash. The following have been reported rarely: photosensitivity reaction. The following have been reported very rarely: alopecia, angioedema, fixed eruption, photosensitive dermatitis, petechia, urticaria.

The following have been reported rarely, asthenia (general feeling of weakness, tiredness), death.

back pain, chest pain, pain, pain in extremities, moniliasis.

dyspnea. The following have been reported very rarely: hiccup, hyperventilation, increased cough, larynx edema, lung edema, lung hemorrhage, pharyngitis, stridor, voice alteration.

thrombophlebitis, injection site reaction. The following have been reported very rarely: burning, erythema, pain, paresthesia, and swelling.

hyperglycemia.

albuminuria, alkaline phosphatase increased, ALT increased, AST increased, bilirubinemia, BUN (urea) increased, cholestatic parameters increased, decreased creatinine clearance, gamma-GT increased, hypercholesteremia, hyperuricemia, increased sedimentation rate, lactic dehydrogenase increased, NPN increased, transaminases increased. The following have been reported rarely: acidosis, amylase increased, crystalluria, electrolyte abnormality, haematuria, hypercalcemia, hypocalcemia and lipase increased.

The following additional adverse events, in alphabetical order, regardless of incidence or relationship to drug, have been reported during clinical trials and from worldwide post-marketing experience in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy durations, and in all indications): arrhythmia, atrial flutter, bleeding diathesis, bronchospasm, C. difficile associated diarrhea, candiduria, cardiac murmur, cardiopulmonary arrest, cardiovascular collapse, cerebral thrombosis, chills, delirium, drowsiness, dysphasia, edema (conjunctivae, hands, lips, lower extremities, neck), epistaxis, exfoliative dermatitis, fever, gastrointestinal bleeding, gout (flare up), gynecomastia, hearing loss, hemoptysis, hemorrhagic cystitis, hyperpigmentation, joint stiffness, lightheadedness, lymphadenopathy, manic reaction, myoclonus, nystagmus, pain (arm, breast, epigastric, foot, jaw, neck, oral mucosa), paranoia, phobia, pleural effusion, polyuria, postural hypotension, pulmonary embolism, purpura, QT prolongation (frequency <1 per million), renal calculi, respiratory arrest, respiratory distress, restlessness, rhabdomyolysis, torsades de pointes (frequency <1 per million), toxic psychosis, unresponsiveness, urethral bleeding, urination (frequent), ventricular ectopy, ventricular fibrillation (frequency <1 per million), ventricular tachycardia (frequency <1 per million), vesicles, visual acuity (decreased) and visual disturbances (flashing lights, change in color perception, overbrightness of lights).

albuminuria, hematuria. The following have been reported rarely: abnormal kidney function, acute kidney failure, dysuria, leukorrhea, nephritis interstitial, urinary retention, vaginitis, vaginal moniliasis.

rash. The following have been reported rarely: allergic reaction, anaphylactic/anaphylactoid reactions including facial, vascular and laryngeal edema, drug fever, vasculitis (petechia, haemorrhagic bullae, papules, crust formation), hepatitis, interstitial nephritis, petechia (punctuate skin hemorrhages), pruritus, serum sickness-like reaction, Stevens-Johnson syndrome (potentially life-threatening). The following have been reported very rarely: shock (anaphylactic; life-threatening), pruritic rash, erythema multiforme (minor), erythema nodosum, major liver disorders including hepatic necrosis (very rarely progressing to life threatening hepatic failure), epidermal necrolysis (Lyell syndrome, potentially life-threatening).

The following have been reported rarely: achiness, arthralgia (joint pain), joint disorder (joint swelling), pain in the extremities, partial or complete tendon rupture (predominantly achilles tendon), tendonitis (predominantly achillotendonitis), myalgia (muscular pain), and very rarely myasthenia (exacerbation of symptoms of myasthenia gravis).

There have been 54 reports of arthropathies with CIPRO. Ten of these reports involved children. Arthralgia was usually the first symptom which led to rapid assessment and withdrawal of the drug. No irreversible arthropathies have been observed.

agitation, confusion, convulsion, dizziness, hallucinations, headache, hypesthesia, increased sweating, insomnia, somnolence, tremor (trembling). The following have been reported rarely: paresthesia (peripheral paralgesia). The following have been reported very rarely: abnormal dreams (nightmares), anxiety, apathy, ataxia, depersonalization, depression, diplopia, hemiplegia, hyperesthesia, hypertonia, increase of intracranial pressure, meningism, migraine, nervousness, neuritis, polyneuritis, sleep disorder, twitching, grand mal convulsion, abnormal (unsteady) gait, psychosis, intracranial hypertension. In some instances, these reactions occurred after the first administration of CIPRO. In these instances, CIPRO is to be discontinued and the doctor should be informed immediately.

dysmenorrhea, hematuria, kidney function abnormal, vaginitis.

Ciprofloxacin: Other Formulations: The following adverse drug reactions have been reported during clinical trials and subsequent post-marketing surveillance with other formulations of ciprofloxacin.

In patients treated orally with CIPRO (tablet and suspension), the most frequently reported events, possibly, probably drug-related were: nausea (1.3%), and diarrhea (1.0%).

In patients treated with CIPRO I.V., the most frequently reported events, possibly, probably drug-related were: rash (1.8%), diarrhea (1.0%), and injection site pain (l.0%).

Events possibly or probably drug-related occurring at a frequency of less than 1% with CIPRO (ciprofloxacin) tablets (immediate release formulation) oral and CIPRO I.V. treatment during clinical trials and subsequent post-marketing surveillance are as follows:

abnormal dreams, depersonalization, depression, hypertonia, incoordination, insomnia, somnolence, tremor, vertigo.

agranulocytosis, anaemia, eosinophilia, leukopenia (granulocytopenia), leukocytopenia, leukocytosis, pancytopenia. The following have been reported very rarely: altered prothrombin levels/INR, hemolytic anaemia, marrow depression (life threatening), pancytopenia (life threatening), thrombocytemia (thrombocytosis).

palpitation, phlebitis, (thrombo)-phlebitis, tachycardia. The following have been reported very rarely (<0.01%): angina pectoris, atrial fibrillation, cardiac arrest, cerebrovascular disorder, electrocardiogram abnormality, hot flashes, hypertension, hypotension, kidney vasculitis, myocardial infarct, pericarditis, pulmonary embolus, substernal chest pain, syncope (fainting), vasodilation (hot flushes).

creatinine increased. The following have been reported rarely: edema (face), hyperglycemia.

In the event of acute excessive oral overdosage, reversible renal toxicity, arthralgia, myalgia and CNS symptoms have been reported.

Therefore, apart from routine emergency measures, it is recommended to monitor renal function and to administer magnesium- or calcium-containing antacids which reduce the absorption of ciprofloxacin and to maintain adequate hydration. Based on information obtained from subjects with chronic renal failure, only a small amount of ciprofloxacin (<10%) is removed from the body after hemodialysis or peritoneal dialysis.

The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase of systemic ciprofloxacin exposure.

No dosage adjustment based on age alone is necessary in elderly patients. Since ciprofloxacin is substantially excreted by the kidney, the risk of adverse reactions may be greater in patients with impaired renal function. No significant accumulation of ciprofloxacin is anticipated in elderly subjects with renal impairment who take CIPRO XL 500 mg, therefore, no reductions in dosage are required.

However, in patients with renal impairment, where CIPRO XL 1000 mg once daily is the appropriate dose, dosage may need to be reduced to CIPRO XL 500 mg once daily (see Dosage, Impaired Renal Function).

CIPRO XL should be administered at least 2 hours before or 6 hours after antacids and mineral supplements containing magnesium or aluminum, as well as sucralfate, Videx (didanosine) chewable/buffered tablets or pediatric powder, metal cations such as iron, and multivitamin preparations with zinc (see Precautions, Drug Interactions).

Although CIPRO XL may be taken with meals that include milk, simultaneous administration with dairy products alone, or with calcium-fortified products should be avoided, since decreased absorption is possible. It is recommended that CIPRO XL be administered at least 2 hours before or 2 hours after substantial calcium intake (>800 mg). CIPRO XL should be swallowed whole. Tablets should not be split, crushed or chewed (see Precautions, Drug Interactions).

Based on pharmacokinetic data, no dosage adjustment is required with CIPRO XL in patients with stable chronic cirrhosis (with mild to moderate hepatic impairment). The kinetics of ciprofloxacin in patients with acute hepatic insufficiency and stable chronic cirrhosis (with severe hepatic impairment), however, have not been elucidated.

CIPRO XL 500 mg: Based on pharmacokinetic data, no dosage adjustment is required with CIPRO XL 500 mg.

CIPRO XL 1000 mg: For complicated urinary tract infections or acute uncomplicated pyelonephritis, where 1000 mg is the appropriate dose, the dosage of CIPRO XL should be reduced to 500 mg CIPRO XL once daily in patients with creatinine clearance below 30 mL/min. This recommendation is based on pharmacokinetic modeling. Clinical studies with CIPRO XL have not been performed in patients with impaired renal function. For patients on hemodialysis or peritoneal dialysis, administer CIPRO XL after the dialysis procedure is completed.