Included as part of the PRECAUTIONS section.
Tendinopathy and Tendon Rupture
Fluoroquinolones, including Proquin XR (ciprofloxacin cipro hcl), are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture 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. Factors, in addition to age and corticosteroid use, 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. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Proquin XR (ciprofloxacin hcl) should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug [see ADVERSE REACTIONS].
Exacerbation of Myasthenia Gravis
Fluoroquinolones, including Proquin XR (ciprofloxacin hcl), have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid Proquin XR (ciprofloxacin hcl) in patients with known history of myasthenia gravis. [See PATIENT INFORMATION and ADVERSE REACTIONS/Reported Post-Marketing Adverse Events with Other Formulations of Ciprofloxacin].
Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with fluoroquinolones, including ciprofloxacin. These reactions often 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. Proquin XR (ciprofloxacin hcl) should be discontinued immediately 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 [see ADVERSE REACTIONS].
Other Serious and Sometimes Fatal Reactions
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, 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 (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome);
- vasculitis; arthralgia; myalgia; serum sickness;
- allergic pneumonitis
- inertstitial nephritis; acute renal insufficiency or failure;
- hepatitis; jaundice; acute hepatic necrosis or failure;
- anemia, including hemolytic and apalstic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hemtologic abnormalities.
- The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see ADVERSE REACTIONS].
Serious and fatal reactions have been reported in patients receiving theophylline concurrently with fluoroquinolones, including ciprofloxacin. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by Proquin XR (ciprofloxacin hcl) cannot be eliminated. If concomitant use cannot be avoided, serum concentrations of theophylline should be monitored and dosage adjustments made as appropriate [see DRUG INTERACTIONS].
Central Nervous System Effects
Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause CNS events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. The 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 that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g., certain drug therapy, renal dysfunction) [see ADVERSE REACTIONS, DRUG INTERACTIONS].
Clostridium difficile-Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Proquin XR (ciprofloxacin hcl), 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 strains 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 represent with diarrhea following antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated [see ADVERSE REACTIONS].
Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dyesthesias, and weakness have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy, including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position, sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition [see ADVERSE REACTIONS].
Arthropathic Effects in Animals
Ciprofloxacin, as with other members of the quinolone class, causes arthropathy and/or chondroplasia in immature dogs. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. The relevance of these findings to the clinical use of ciprofloxacin is unknown. [see Use In Specific Populations, Nonclinical Toxicology].
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., 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].
Development of Drug Resistant Bacteria
Prescribing Proquin XR (ciprofloxacin hcl) 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.
Patient Counseling Information
See FDA-Approved Medication Guide
Use Only for Uncomplicated Urinary Tract Infection
Inform patients that Proquin XR (ciprofloxacin hcl) is only approved to treat uncomplicated urinary tract infections and to contact their healthcare provider if they do not feel better or if they develop fever and back pain while or after taking Proquin XR.
Instruct patients 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 Proquin XR (ciprofloxacin hcl) treatment. The risk of severe tendon disorders 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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
Myasthenia Gravis Syndrome
Fluoroquinolones like Proquin XR (ciprofloxacin hcl) may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if you have any worsening muscle weakness or breathing problems.
Inform patients that ciprofloxacin may be associated with hypersensitivity reactions; even following a single dose. Instruct patients to discontinue Proquin XR and contact their healthcare provider at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (e.g., swelling of lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction [see WARNINGS AND PRECAUTIONS].
Inform patients that convulsions have been reported in patients taking fluoroquinolones, including ciprofloxacin and to notify their physician before taking this drug if they have a history of convulsions [see WARNINGS AND PRECAUTIONS].
Neurologic Adverse Effects (e.g., dizziness, lightheadedness)
Instruct patients to wait to see how they react to Proquin XR (ciprofloxacin hcl) before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination [see WARNINGS AND PRECAUTIONS].
Clostridium difficile-Associated Diarrhea
Inform patients 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, instruct patients to contact their physician as soon as possible [see WARNINGS AND PRECAUTIONS].
Advise patients if symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness develop, they should discontinue treatment and contact their physician [see WARNINGS AND PRECAUTIONS].
Advise to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking Proquin XR (ciprofloxacin hcl). If patients need to be outdoors when taking Proquin XR (ciprofloxacin hcl), instruct them to 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, instruct patients to contact their physician [see WARNINGS AND PRECAUTIONS].
Administration with Food, Fluids, and Concomitant Medications
Instruct patients to:
- Take Proquin XR (ciprofloxacin hcl) with a main meal of the day, preferably the evening meal and not to take more than one Proquin XR (ciprofloxacin hcl) tablet per day, even if a dose is missed.
- Take Proquin XR (ciprofloxacin hcl) tablets whole. Never split, crush, or chew tablets.
- Drink fluids liberally while taking Proquin XR (ciprofloxacin hcl) to avoid formation of a highly concentrated urine and crystal formation in the urine.
- Take Proquin XR (ciprofloxacin hcl) at least 4 hours before or 2 hours after antacids and other multivalent cation-containing products. Aluminum or magnesium-containing antacids, sucralfate, VIDEX® (didanosine) chewable buffered tablets or pediatric powder, metal cations such as iron and calcium, and multivitamin preparations containing zinc reduces the absorption of ciprofloxacin.
- Avoid taking Proquin XR (ciprofloxacin hcl) with dairy products (like milk or yogurt) or calcium-fortified juices alone, since the absorption of ciprofloxacin may be significantly reduced by these products. However, Proquin XR (ciprofloxacin hcl) may be taken with a meal that contains these products.
Instruct patients to inform their healthcare provider if they are taking theophylline. Proquin XR (ciprofloxacin hcl) may increase the effects of theophylline and some other prescription or over-the-counter medications, when taken concurrently with ciprofloxacin.
Instruct patients to inform their healthcare provider if they are taking antacids and other multivalent cation containing prescription or over-the-counter medications. Such products can reduce the absorption of ciprofloxacin [see Administration with Food, Fluids and Concomitant Medications].
Use of Proquin XR (ciprofloxacin hcl) Sample Pack Advise the patient that the sample pack contains only one dose for the first day of treatment with Proquin® XR (ciprofloxacin hcl). Complete treatment requires 3 doses. The patient must fill a prescription for the remaining two doses.
Human Milk Feeding
Advise women to avoid feeding their infants with their milk during treatment with Proquin XR (ciprofloxacin hcl). Women should either discontinue feeding or pump and discard their milk during treatment and for 24 hours after the last dose [see Use in Specific Populations].
Antibacterial drugs including Proquin XR (ciprofloxacin hcl) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Proquin XR (ciprofloxacin hcl) is 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 Proquin XR (ciprofloxacin hcl) or other antibacterial drugs in the future [see WARNINGS AND PRECAUTIONS].
Carcinogenesis, Mutagenesis, Impairment of Fertility
Rodent carcinogenicity studies were not required. Two in vitro mutagenicity tests were conducted with ciprofloxacin:
Bacterial Reverse Mutation Assay; negative for mutagenicity in the presence and absence of an S9 metabolic activation system.
Chinese Hamster Ovary (CHO) Chromosomal Aberration Assay; positive for inducing chromosomal aberrations.
In addition to the in vitro genotoxicity assays, an in vivo rat micronucleus study with ciprofloxacin was negative.
Fertility studies performed with male and female rats at oral doses of ciprofloxacin up to 600 mg/kg/day (approximately 10-fold the recommended 500 mg therapeutic dose based upon body surface area) revealed no evidence of impairment.
Use In Specific Populations
Pregnancy (Teratogenic Effects. Pregnancy Category C)
There are no adequate and well-controlled studies of Proquin XR (ciprofloxacin hcl) in pregnant women. However, human data on more than 500 infants from two controlled cohort studies do not show an increased risk for major congenital malformations overall in infants exposed to ciprofloxacin during the first trimester of pregnancy or at other times during pregnancy. The risks to a developing musculoskeletal system were not fully evaluated. Animal studies in rats and rabbits demonstrated variations or anomalies in fetal skeletal development and increased embryo-fetal mortality. These effects occurred at clinically relevant doses but also in the presence of maternal toxicity. Proquin XR (ciprofloxacin hcl) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
A controlled, prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. Following in-utero exposure to fluoroquinolones during embryogenesis, there was no associated 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. Rates of spontaneous abortions, prematurity and low birth weight did not differ between the study groups, and there were no clinically significant musculoskeletal dysfunctions up to one year of age in ciprofloxacin exposed children.
A controlled, retrospective cohort study of more than 30,000 infants enrolled in Medicaid included 588 infants exposed to ciprofloxacin during pregnancy (average 8 day exposure), and 439 exposures occurred during the first trimester. Compared to a control group with no antibiotic exposure and a control group with exposure to a nonteratogenic antibiotic commonly used during pregnancy, infants exposed to ciprofloxacin during the first trimester (or other times during pregnancy) did not demonstrate an increased risk for major congenital malformations overall. The study was powered to rule out a two fold increased risk for major malformations. The study was not designed to fully assess abnormal musculoskeletal development.
Another prospective observational 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 the background rates for congenital malformations in the general population. There was no specific patterns of congenital abnormalities and no clear adverse reactions due to in-utero exposure to ciprofloxacin.
Published data do not suggest increased rates of prematurity, spontaneous abortions, or birth weight in women exposed to ciprofloxacin during pregnancy, but these data are very limited.
In embryo/fetal developmental toxicity studies, pregnant rats and rabbits received oral doses of ciprofloxacin up to 600 mg/kg/day in rats and 30 mg/kg/day in rabbits. In rats, fetal skeletal variations occurred at the maternally toxic dose of 600 mg/kg/day (approximately 1.8-fold the recommended 500 mg therapeutic dose based upon plasma AUC measure of systemic exposure). In pregnant rabbits, the maternally toxic 30 mg/kg/day dose resulted in abortions and reductions in body weight gain. Embryo/fetal lethality and skeletal developmental effects also occurred in rabbits at this dose level (approximately 1.2-fold the recommended therapeutic dose based upon body surface area), while the maternally toxic 10 mg/kg/day dose level did not induce embryo/fetal developmental effects. A peri/postnatal developmental toxicity study conducted in pregnant/lactating female rats exhibited no developmental effects in offspring at the highest dose level of 600 mg/kg/day. Both the 300 and 600 mg/kg/day dose levels were maternally toxic to the pregnant dams based upon slight body weight gain reduction. There was no evidence of compound-related fetal malformation in any of the reproductive toxicity studies.
Ciprofloxacin is excreted in human milk. In one study, ten lactating women received oral ciprofloxacin 750 mg every 12 hours. Peak human milk concentrations of ciprofloxacin following the third dose averaged 3.79 mcg/mL (S.D. 1.26), and these levels decreased to a mean of 0.02 mcg/mL at 24 hours after the third dose. Based on these concentrations, the maximum daily infant dose of ciprofloxacin through human milk is about 0.569 mg/kg per day, about 2.8% of the approved 20 mg/kg dose in children one year of age or older.
Because of the potential for serious adverse reactions in infants from ciprofloxacin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of ciprofloxacin to the mother. During short courses of therapy, nursing mothers may express and discard milk. Human milk feeding can resume 24 hours after the last dose of Proquin XR (ciprofloxacin hcl).
The safety and effectiveness of Proquin XR (ciprofloxacin hcl) in pediatric patients and adolescents less than 18 years of age have not been established. Quinolones, including ciprofloxacin, cause arthropathy in juvenile animals [see Nonclinical Toxicology]
Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as Proquin XR. 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 Proquin XR (ciprofloxacin hcl) to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue Proquin XR (ciprofloxacin hcl) and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].
Clinical experience with Proquin XR (ciprofloxacin hcl) did not include sufficient number of subjects 65 years of age or older to determine whether they respond differently than younger subjects. Reported clinical experience with other formulations of ciprofloxacin has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is 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 [see CLINICAL PHARMACOLOGY].
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using Proquin XR with concomitant drugs that can result in prolongation of the QT interval (e.g. class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
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 mild to moderate renal impairment. The efficacy of Proquin XR (ciprofloxacin hcl) has not been studied in patients with severe renal impairment [see CLINICAL PHARMACOLOGY].
No dosage adjustment is required with Proquin XR (ciprofloxacin hcl) in patients with stable chronic cirrhosis. However, the pharmacokinetics of ciprofloxacin in patients with acute hepatic impairment has not been fully elucidated [see CLINICAL PHARMACOLOGY].
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