Data from FDA - Curated by EPG Health - Last updated 20 December 2016

Indication(s)

INDICATIONS AND USAGE Ciprofloxacin extended-release tablets are indicated only for the treatment of urinary tract infections, including acute uncomplicated pyelonephritis, caused by susceptible isolates of the designated microorganisms as listed below.

Ciprofloxacin extended-release tablets and ciprofloxacin immediate-release tablets are not interchangeable.

Please see DOSAGE AND ADMINISTRATION for specific recommendations.

Uncomplicated Urinary Tract Infections (Acute Cystitis) caused by Escherichia coli, Proteus mirabilis, vancomycin-susceptible Enterococcus faecalis, or Staphylococcus saprophyticus.

Complicated Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, vancomycin-susceptible Enterococcus faecalis, Proteus mirabilis, or Pseudomonas aeruginosa *.

Acute Uncomplicated Pyelonephritis caused by Escherichia coli.

* Treatment of infections due to this organism in the organ system was studied in fewer than 10 patients.

THE SAFETY AND

EFFICACY OF

CIPROFLOXACIN EXTENDED-RELEASE TABLETS IN TREATING INFECTIONS OTHER THAN URINARY TRACT INFECTIONS HAS NOT BEEN DEMONSTRATED. 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 extended-release tablets may be initiated before results of these tests are known; once results become available appropriate therapy should be continued.

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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ciprofloxacin extended-release tablets and other antibacterial drugs, ciprofloxacin extended-release tablets should be used only to treat or prevent 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.

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Advisory information

contraindications
CONTRAINDICATIONS Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components. Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug Interactions .)
Special warnings and precautions

PRECAUTIONS General 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.

(See ANIMAL PHARMACOLOGY.

) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic.

Alkalinity of the urine should be avoided in patients receiving ciprofloxacin.

Patients should be well hydrated to prevent the formation of highly concentrated urine.

Quinolones, including ciprofloxacin, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia.

(See WARNINGS, Information for Patients, and Drug Interactions.

) 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 after sun or UV light exposure.

Therefore, excessive exposure to these sources of light should be avoided.

Drug therapy should be discontinued if phototoxicity occurs (see ADVERSE REACTIONS).

Prescribing ciprofloxacin extended-release tablets 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.

Information for Patients: Patients should be advised: •To contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue ciprofloxacin extended-release tablets treatment.

The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.

•That fluoroquinolones like ciprofloxacin extended-release tablets may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems.

Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems.

•That antibacterial drugs including ciprofloxacin extended-release tablets should only be used to treat bacterial infections.

They do not treat viral infections (e.g., the common cold).

When ciprofloxacin extended-release tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ciprofloxacin extended-release tablets or other antibacterial drugs in the future.

•That ciprofloxacin extended-release tablets may be taken with or without meals and to drink fluids liberally.

As with other quinolones, concurrent administration with magnesium/aluminum antacids, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or with other products containing calcium, iron, or zinc should be avoided.

Ciprofloxacin extended-release tablets may be taken two hours before or six hours after taking these products.

(See CLINICAL PHARMACOLOGY, Drug-drug Interactions, DOSAGE AND ADMINISTRATION, and PRECAUTIONS, Drug Interactions.

) Ciprofloxacin extended-release tablets should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, ciprofloxacin extended-release tablets may be taken with a meal that contains these products.

(See CLINICAL PHARMACOLOGY, Drug-drug Interactions, DOSAGE AND ADMINISTRATION, and PRECAUTIONS, Drug Interactions.

) •If the patient should forget to take ciprofloxacin extended-release tablets at the usual time, he/she may take the dose later in the day.

Do not take more than one ciprofloxacin extended-release tablet per day even if a patient misses a dose.

Swallow the ciprofloxacin extended-release tablet whole.

DO NOT SPLIT, CRUSH, OR CHEW THE TABLET. •That ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue ciprofloxacin extended-release tablets at the first sign of a skin rash or other allergic reaction.

•That photosensitivity/phototoxicity has been reported in patients receiving quinolones.

Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones.

If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician.

If a sunburn-like reaction or skin eruption occurs, patients should contact their physician.

•That peripheral neuropathies have been associated with ciprofloxacin use, that symptoms may occur soon after initiation of therapy and may be irreversible.

If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should immediately discontinue ciprofloxacin and contact their physician.

•That ciprofloxacin extended-release tablets may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.

•That ciprofloxacin increases the effects of tizanidine (Zanaflex®).

Patients should not use ciprofloxacin if they are already taking tizanidine.

•That ciprofloxacin extended-release tablets may increase the effects of theophylline and caffeine.

There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.

•That convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to notify their physician before taking ciprofloxacin extended-release tablets if there is a history of this condition.

•That diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.

Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.

If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

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 bid for 3 days).

The hypotensive and sedative effects of tizanidine were also potentiated.

Concomitant administration of tizanidine and ciprofloxacin is contraindicated.

(See CONTRAINDICATIONS.

) Theophylline As with some other quinolones, 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 WARNINGS.

) If concomitant use can not be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

Other Xanthine Derivatives Some quinolones, including ciprofloxacin, have 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.

On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline) containing products, elevated serum concentrations of these xanthine derivatives were reported.

Chelation Complex Formation Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, 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.

Ciprofloxacin extended-release tablets should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, 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.

(See CLINICAL PHARMACOLOGY, Drug-drug Interactions, PRECAUTIONS, Information for Patients, and DOSAGE AND ADMINISTRATION.)

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

Omeprazole Concomitant administration of a single tablet dose of 500 mg ciprofloxacin and once-daily administration of 20 mg omeprazole pretreatment for 4 days resulted in a 16 % reduction of mean Cmax and mean AUC of ciprofloxacin (See CLINICAL PHARMACOLOGY, Drug-drug Interactions.

) Phenytoin Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.

To avoid the loss of seizure control associated with decreased phenytoin levels, and to prevent phenytoin overdose-related undesirable effects when ciprofloxacin is discontinued in patients receiving both agents, monitoring of phenytoin therapy, including phenytoin serum concentration measurements, is recommended during and shortly after coadministration of ciprofloxacin extended-release tablets with phenytoin.

Oral Antidiabetic Agents Hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent (see ADVERSE REACTIONS).

The concomitant administration of ciprofloxacin with glyburide has, on rare occasions, resulted in severe hypoglycemia.

Metronidazole The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.

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

Oral Anticoagulants Simultaneous administration of ciprofloxacin with an oral anticoagulantmay augment the effect of the anticoagulant.

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.

Prothrombin time and INR should be monitored frequently during and shortly after coadministration of ciprofloxacin with an oral anticoagulant (for example, warfarin).

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.

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 ciprofloxacin therapy is indicated.

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.

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 of mean AUC and a 2.5-fold increase in mean Cmax of duloxetine.

Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.

NSAIDs 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.

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 side effects and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin.

(See WARNINGS, Cytochrome P450.

) 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 and an increase in side effects related to lidocaine may occur upon concomitant administration.

Clozapine Following concomitant administration of 250 mg ciprofloxacin with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29 % and 31 %, respectively.

Careful monitoring of clozapine associated adverse effects and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.

(See WARNINGS.)

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.

Therefore, sildenafil should be used with caution when coadministered with ciprofloxacin.

Drugs known to prolong QT interval Precaution should be taken when using ciprofloxacin concomitantly with drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) as ciprofloxacin may have an additive effect on the QT interval (see WARNINGS and PRECAUTIONS, Geriatric Use).

Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in_vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below: Salmonella/Microsome Test (Negative) E. coli DNA Repair

Assay (Negative) Mouse

Lymphoma Cell Forward Mutation Assay (Positive) Chinese Hamster V79Cell HGPRT Test (Negative) Syrian Hamster Embryo Cell Transformation Assay (Negative) Saccharomyces cerevisiae Point Mutation Assay (Negative) Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative) Rat Hepatocyte DNA Repair Assay (Positive) Thus, 2 of the 8 tests were positive, but results of the following 3 in_vivo test systems gave negative results: Rat Hepatocyte DNA Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice) Ciprofloxacin was not carcinogenic or tumorigenic in 2-year carcinogenicity studies with rats and mice at daily oral dose levels of 250 and 750 mg/kg, respectively (approximately 2 and 3-fold greater than the 1000 mg daily human dose based upon body surface area).

Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control.

Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin.

The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to the maximum recommended daily human dose of 1000 mg based upon mg/ m2), as opposed to 34 weeks when animals were treated with both UVA and vehicle.

The times to development of skin tumors ranged from 16 to 32 weeks in mice treated concomitantly with UVA and other quinolones.

In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors.

There are no data from similar models using pigmented mice and/or fully haired mice.

The clinical significance of these findings to humans is unknown.

Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (1 times the highest recommended daily human dose of 1000 mg based upon body surface area) revealed no evidence of impairment.

Pregnancy Teratogenic Effects.

Pregnancy Category C There are no adequate and well-controlled studies in pregnant women.

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 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 to 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.

Ciprofloxacin should not be used during pregnancy unless potential benefit justifies the potential risk to both fetus and mother (see WARNINGS).

Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.7 and 0.4 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, ciprofloxacin (30 and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose.

After intravenous administration of doses up to 20 mg/kg, 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.

Pediatric Use Safety and effectiveness of ciprofloxacin extended-release tablets in pediatric patients and adolescents less than 18 years of age have not been established.

Ciprofloxacin causes arthropathy in juvenile animals.

(See WARNINGS.)

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 extended-release tablets.

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 extended-release tablets to elderly patients especially those on corticosteroids.

Patients should be informed of this potential side effect and advised to discontinue ciprofloxacin extended-release tablets and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (See BOXED WARNING, WARNINGS, and ADVERSE REACTIONS).

In a large, prospective, randomized ciprofloxacin extended-release tablets clinical trial in complicated urinary tract infections, 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 clinical experience with other formulations of ciprofloxacin has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals can not 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.

(See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.

) In general, elderly patients may be more susceptible to drug-associated effects on the QT interval.

Therefore, precaution should be taken when using ciprofloxacin extended-release tablets 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 (for example, known QT prolongation, uncorrected hypokalemia).

Adverse reactions

ADVERSE REACTIONS Clinical trials in patients with urinary tract infections enrolled 961 patients treated with 500 mg or 1000 mg ciprofloxacin extended-release tablets.

Most adverse events reported were described as mild to moderate in severity and required no treatment.

The overall incidence, type and distribution of adverse events were similar in patients receiving both 500 mg and 1000 mg of ciprofloxacin extended-release tablets.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug can not be directly compared to rates observed in clinical trials of another drug and may not reflect the rates observed in practice.

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 uncomplicated urinary tract infection, ciprofloxacin extended-release tablets (500 mg once daily) in 444 patients was compared to ciprofloxacin immediate-release tablets (250 mg twice daily) in 447 patients for 3 days.

Discontinuations due to adverse reactions thought to be drug-related occurred in 0.2 % (1/444) of patients in the ciprofloxacin extended-release tablet arm and in 0 % (0/447) of patients in the control arm.

In the clinical trial of complicated urinary tract infection and acute uncomplicated pyelonephritis, 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 extended-release tablet arm and in 2.3 % (12/518) of patients in the control arm.

The most common reasons for discontinuation in the ciprofloxacin extended-release tablet 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 extended-release tablets patients, regardless of drug relationship: nausea (4 %), headache (3 %), dizziness (2 %), diarrhea (2 %), vomiting (2 %) and vaginal moniliasis (2 %).

Adverse events, judged by investigators to be at least possibly drug-related, occurring in greater than or equal to 1 % of all ciprofloxacin extended-release tablet 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.

Additional uncommon events, judged by investigators to be at least possibly drug-related, that occurred in less than 1 % of ciprofloxacin extended-release tablet treated patients were: BODY AS A WHOLE: abdominal pain, asthenia, malaise, photosensitivity reaction CARDIOVASCULAR: bradycardia, migraine, syncope DIGESTIVE: anorexia, constipation, dry mouth, flatulence, liver function tests abnormal, thirst HEMIC/LYMPHATIC: prothrombin decrease CENTRAL NERVOUS SYSTEM: convulsive seizures (including status epilepticus) abnormal dreams, depersonalization, depression (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts and attempted or completed suicide), hypertonia, incoordination, insomnia, somnolence, tremor, vertigo METABOLIC: hyperglycemia

hypoglycemia SKIN/HYPERSENSIVITY: dry skin, maculopapular rash, photosensitivity/phototoxicity reactions, pruritus, rash, skin disorder, urticaria, vesiculobullous rash SPECIAL SENSES: diplopia, taste perversion UROGENITAL: dysmenorrhea, hematuria, kidney function abnormal, vaginitis Post-Marketing Adverse Event Reports: The following adverse events have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin.

Because these reactions have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or a causal relationship to drug exposure.

The events in alphabetical order are: abnormal gait, achiness, acidosis, acute generalized exanthematous pustulosis (AGEP), agitation, agranulocytosis, allergic reactions (ranging from urticaria to anaphylactic reactions and including life-threatening anaphylactic shock), amylase increase, anemia, angina pectoris, angioedema, anosmia, anxiety, arrhythmia, arthralgia, ataxia, atrial flutter, bleeding diathesis, blurred vision, bronchospasm, C. difficile associated diarrhea, candidiasis (cutaneous, oral), candiduria, cardiac murmur, cardiopulmonary arrest, cardiovascular collapse, cerebral thrombosis, chills, cholestatic jaundice, chromatopsia, confusion, convulsion, delirium, drowsiness, dysphagia, dysphasia, dyspnea, edema (conjunctivae, face, hands, laryngeal, lips

lower extremities, neck, pulmonary), epistaxis, erythema multiforme, erythema nodosum, exfoliative dermatitis, fever, fixed eruptions, flushing, gastrointestinal bleeding, gout (flare up), grand mal convulsion, gynecomastia, hallucinations, hearing loss, hemolytic anemia, hemoptysis, hemorrhagic cystitis, hepatic failure (including fatal cases), hepatic necrosis, hepatitis, hiccup, hyperesthesia, hyperpigmentation, hypertension, hypertonia, hypesthesia, hypotension, ileus, International Normalized Ratio (INR) increased (in patients treated with Vitamin K antagonists), interstitial nephritis, intestinal perforation, jaundice, joint stiffness, lethargy, lightheadedness, lipase increase, lymphadenopathy, manic reaction, marrow depression, migraine, moniliasis (oral

gastrointestinal, vaginal), myalgia, myasthenia, exacerbation of myasthenia gravis, myocardial infarction, myoclonus, nephritis, nightmares, nystagmus, oral ulceration, pain (arm, back, breast, chest, epigastric, eye, extremities, foot, jaw, neck, oral mucosa), palpitation, pancreatitis, pancytopenia, paranoia, paresthesia, peripheral neuropathy that may be irreversible, perspiration (increased), petechia, phlebitis, phobia, photosensitivity/phototoxicity reaction, pleural effusion, polyuria, postural hypotension, prothrombin time prolongation, pseudomembranous colitis (the onset of symptoms may occur during or after antimicrobial treatment), pulmonary embolism, purpura, renal calculi, renal failure, respiratory arrest, respiratory distress, restlessness

serum sickness-like reaction, Stevens-Johnson syndrome, sweating, tachycardia, taste loss, tendinitis, tendon rupture, tinnitus, torsade de pointes, toxic epidermal necrolysis (Lyell 's syndrome), toxic psychosis, QT prolongation, twitching, unresponsiveness, urethral bleeding, urinary retention, urination (frequent), uveitis, vaginal pruritus, vasculitis, ventricular ectopy, vesicles, visual acuity (decreased), visual disturbances (flashing lights, change in color perception, overbrightness of lights).

Laboratory Changes: The following adverse laboratory changes, in alphabetical order, regardless of incidence or relationship to drug, have been reported in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy durations, and all indications): Decreases in blood glucose, BUN, hematocrit, hemoglobin, leukocyte counts, platelet counts, prothrombin time, serum albumin, serum potassium, total serum protein, uric acid.

Increases in alkaline phosphatase, ALT (SGPT), AST (SGOT), atypical lymphocyte counts, blood glucose, blood monocytes, BUN, cholesterol, eosinophil counts, LDH, platelet counts, prothrombin time, sedimentation rate, serum amylase, serum bilirubin, serum calcium, serum cholesterol, serum creatine phosphokinase, serum creatinine, serum gamma-glutamyl transpeptidase (GGT), serum potassium, serum theophylline (in patients receiving theophylline concomitantly), serum triglycerides, uric acid.

Others: albuminuria, change in serum phenytoin, crystalluria, cylindruria, immature WBCs, leukocytosis, methemoglobinemia, pancytopenia.

Usage information

Dosing and administration

DOSAGE AND ADMINISTRATION Ciprofloxacin Extended-Release Tablets and ciprofloxacin immediate-release tablets are not interchangeable.

Ciprofloxacin extended-release tablets should be administered orally once daily as described in the following Dosage Guidelines table: DOSAGE GUIDELINES Indication Unit Dose Frequency Usual Duration Uncomplicated Urinary Tract Infection (Acute Cystitis) 500 mg Q24h 3 Days Complicated Urinary Tract Infection 1000 mg Q24h 7-14 Days Acute Uncomplicated Pyelonephritis 1000 mg Q24h 7-14 Days Patients whose therapy is started with ciprofloxacin I.V. for urinary tract infections may be switched to ciprofloxacin extended-release tablets when clinically indicated at the discretion of the physician.

Ciprofloxacin extended-release tablets 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.

Although ciprofloxacin extended-release tablets may be taken with meals that include milk, concomitant administration with dairy products alone, or with calcium-fortified products should be avoided, since decreased absorption is possible.

A 2-hour window between substantial calcium intake (> 800 mg) and dosing with ciprofloxacin extended-release tablets are recommended.

Ciprofloxacin extended-release tablets should be swallowed whole.

DO NOT SPLIT, CRUSH, OR CHEW THE TABLET. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions, PRECAUTIONS, Drug Interactions and Information for Patients.)

Impaired Renal Function: 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 urinary tract infections receiving 500 mg ciprofloxacin extended-release tablets.

In patients with complicated urinary tract infections and acute uncomplicated pyelonephritis, who have a creatinine clearance of?

30 mL/min, the dose of ciprofloxacin extended-release tablets should be reduced from 1000 mg to 500 mg daily.

The use of ciprofloxacin 1000 mg extended-release tablets are not recommended in this patient population.

For patients on hemodialysis or peritoneal dialysis, administer ciprofloxacin extended-release tablets after the dialysis procedure is completed (maximum dose should be ciprofloxacin 500 mg extended-release tablets q 24 h).

The use of ciprofloxacin 1000 mg extended-release tablets are not recommended in this patient population.

(See CLINICAL PHARMACOLOGY, Special Populations, and PRECAUTIONS, Geriatric Use.

) For patients on continuous ambulatory peritoneal dialysis (CAPD), the maximum dose should be 500 mg q 24h.

Impaired Hepatic Function: No dosage adjustment is required with ciprofloxacin extended-release tablets in patients with stable chronic cirrhosis.

The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated.

(See CLINICAL PHARMACOLOGY, Special Populations.

) Children and Adolescents Dosing in children (less than 18 years of age) with impaired renal or hepatic function has not been studied.

Pregnancy and lactation

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.

Interactions

Drug Interactions 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 bid for 3 days).

The hypotensive and sedative effects of tizanidine were also potentiated.

Concomitant administration of tizanidine and ciprofloxacin is contraindicated.

(See CONTRAINDICATIONS.

) Theophylline As with some other quinolones, 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 WARNINGS.

) If concomitant use can not be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

Other Xanthine Derivatives Some quinolones, including ciprofloxacin, have 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.

On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline) containing products, elevated serum concentrations of these xanthine derivatives were reported.

Chelation Complex Formation Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, 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.

Ciprofloxacin extended-release tablets should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, 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.

(See CLINICAL PHARMACOLOGY, Drug-drug Interactions, PRECAUTIONS, Information for Patients, and DOSAGE AND ADMINISTRATION.)

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

Omeprazole Concomitant administration of a single tablet dose of 500 mg ciprofloxacin and once-daily administration of 20 mg omeprazole pretreatment for 4 days resulted in a 16 % reduction of mean Cmax and mean AUC of ciprofloxacin (See CLINICAL PHARMACOLOGY, Drug-drug Interactions.

) Phenytoin Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.

To avoid the loss of seizure control associated with decreased phenytoin levels, and to prevent phenytoin overdose-related undesirable effects when ciprofloxacin is discontinued in patients receiving both agents, monitoring of phenytoin therapy, including phenytoin serum concentration measurements, is recommended during and shortly after coadministration of ciprofloxacin extended-release tablets with phenytoin.

Oral Antidiabetic Agents Hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent (see ADVERSE REACTIONS).

The concomitant administration of ciprofloxacin with glyburide has, on rare occasions, resulted in severe hypoglycemia.

Metronidazole The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.

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

Oral Anticoagulants Simultaneous administration of ciprofloxacin with an oral anticoagulantmay augment the effect of the anticoagulant.

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.

Prothrombin time and INR should be monitored frequently during and shortly after coadministration of ciprofloxacin with an oral anticoagulant (for example, warfarin).

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.

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 ciprofloxacin therapy is indicated.

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.

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 of mean AUC and a 2.5-fold increase in mean Cmax of duloxetine.

Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.

NSAIDs 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.

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 side effects and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin.

(See WARNINGS, Cytochrome P450.

) 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 and an increase in side effects related to lidocaine may occur upon concomitant administration.

Clozapine Following concomitant administration of 250 mg ciprofloxacin with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29 % and 31 %, respectively.

Careful monitoring of clozapine associated adverse effects and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.

(See WARNINGS.)

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.

Therefore, sildenafil should be used with caution when coadministered with ciprofloxacin.

Drugs known to prolong QT interval Precaution should be taken when using ciprofloxacin concomitantly with drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) as ciprofloxacin may have an additive effect on the QT interval (see WARNINGS and PRECAUTIONS, Geriatric Use).

More information

Category Value
Authorisation number ANDA078166
Agency product number 5E8K9I0O4U
Orphan designation No
Product NDC 10370-107,10370-108
Date Last Revised 17-03-2014
Type HUMAN PRESCRIPTION DRUG
RXCUI 359383
Marketing authorisation holder Par Pharmaceutical, Inc.
Warnings

WARNING:

Fluoroquinolones, including Ciprofloxacin Extended-Release Tablets, are associated with an increased risk of tendinitis and tendon rupture in all ages.

This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants (see WARNINGS).

Fluoroquinolones, including ciprofloxacin extended-release tablets, may exacerbate muscle weakness in persons with myasthenia gravis.

Avoid ciprofloxacin extended-release tablets in patients with known history of myasthenia gravis (see WARNINGS).