Ciprofloxacin Information
Ciprofloxacin ()
Ciprofloxacin ()
Ciprofloxacin () Description
Ciprofloxacin () Injection is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.) administration. Ciprofloxacin () , a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is CHFNO and its chemical structure is:
Ciprofloxacin () is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. Ciprofloxacin () Injection solution is available as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection and contains lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the 0.2% ready-for-use infusion solutions is 3.5 to 4.6.
The plastic container is composed of sterilizable medical grade film (Cryovac® M312 Pharmaceutical Solutions Film). The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period. However, the suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers as well as by tissue culture toxicity studies.
Ciprofloxacin () Clinical Pharmacology
Following 60-minute intravenous infusions of 200 mg and 400 mg Ciprofloxacin () to normal volunteers, the mean maximum serum concentrations achieved were 2.1 and 4.6 mcg/mL, respectively; the concentrations at 12 hours were 0.1 and 0.2 mcg/mL, respectively.
The pharmacokinetics of Ciprofloxacin () are linear over the dose range of 200 to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q 12 h regimen indicates no evidence of drug accumulation.
The absolute bioavailability of oral Ciprofloxacin () is within a range of 70–80% with no substantial loss by first pass metabolism. An intravenous infusion of 400 mg Ciprofloxacin () given over 60 minutes every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg Ciprofloxacin () given over 60 minutes every 8 hours has been shown to produce an AUC at steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V. dose results in a C similar to that observed with a 750-mg oral dose. An infusion of 200 mg Ciprofloxacin () given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.
The serum elimination half-life is approximately 5–6 hours and the total clearance is around 35 L/hr. After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 mcg/mL 0–2 hours after dosing and are generally greater than 15 mcg/mL 8–12 hours after dosing. Following a 400-mg I.V. dose, urine concentrations generally exceed 400 mcg/mL 0–2 hours after dosing and are usually greater than 30 mcg/mL 8–12 hours after dosing. The renal clearance is approximately 22 L/hr. The urinary excretion of Ciprofloxacin () is virtually complete by 24 hours after dosing.
Although bile concentrations of Ciprofloxacin () are several fold higher than serum concentrations after intravenous dosing, only a small amount of the administered dose (
Pharmacokinetic studies of the oral (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. Although the C is increased 16–40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See .)
In patients with reduced renal function, the half-life of Ciprofloxacin () is slightly prolonged and dosage adjustments may be required. (See .)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in Ciprofloxacin () pharmacokinetics have been observed. However, the kinetics of Ciprofloxacin () in patients with acute hepatic insufficiency have not been fully elucidated.
Following a single oral dose of 10 mg/kg Ciprofloxacin () suspension to 16 children ranging in age from 4 months to 7 years, the mean C was 2.4 mcg/mL (range: 1.5 – 3.4 mcg/mL) and the mean AUC was 9.2 mcg*h/mL (range: 5.8 – 14.9 mcg* h/mL). There was no apparent age-dependence, and no notable increase in C or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given intravenous Ciprofloxacin () (10 mg/kg as a 1-hour infusion), the mean C was 6.1 mcg/mL (range: 4.6 – 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL (range: 4.7 – 11.8 mcg/mL) in 10 children between 1 and 5 years of age. The AUC values were 17.4 mcg*h/mL (range: 11.8 – 32.0 mcg*h/mL) and 16.5 mcg*h/mL (range: 11.0 – 23.8 mcg*h/mL) in the respective age groups. These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4–5 hours and the bioavailability of the oral suspension is approximately 60%.
Ciprofloxacin () Microbiology
Ciprofloxacin () has activity against a wide range of gram-negative and gram-positive microorganisms. The bactericidal action of Ciprofloxacin () results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones, including Ciprofloxacin () , is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to Ciprofloxacin () and other quinolones. There is no known cross-resistance between Ciprofloxacin () and other classes of antimicrobials. resistance to Ciprofloxacin () develops slowly by multiple step mutations.
Ciprofloxacin () is slightly less active when tested at acidic pH. The inoculum size has little effect when tested . The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin () has been shown to be active against most strains of the following microorganisms, both and in clinical infections as described in the section of the package insert for Ciprofloxacin () for intravenous infusion.
Ciprofloxacin () Indications And Usage
Ciprofloxacin () injection is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions and patient populations listed below when the intravenous administration offers a route of administration advantageous to the patient. Please see for specific recommendations.
NOTE: Although effective in clinical trials, Ciprofloxacin () is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to .
NOTE: Although effective in clinical trials, Ciprofloxacin () is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues. (See and .) Ciprofloxacin () , like other fluoroquinolones, is associated with arthopathy and histopathological changes in weight-bearing joints of juvenile animals. (See .)
Ciprofloxacin () 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 )
Ciprofloxacin () Warnings
THE SAFETY AND EFFECTIVENESS OF Ciprofloxacin () IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED.
Ciprofloxacin () should be used in pediatric patients (less than 18 years of age) only for infections listed in the section. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed. (See .)
In pre-clinical studies, oral administration of Ciprofloxacin () caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. (See .)
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS Ciprofloxacin () AND THEOPHYLLINE
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.
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:
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 ).
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of , and surgical evaluation should be instituted as clinically indicated.
Ciprofloxacin () Precautions
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (C 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.
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 .) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Some quinolones, including Ciprofloxacin () , have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life.
Some quinolones, including Ciprofloxacin () , have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant Ciprofloxacin () .
The concomitant administration of Ciprofloxacin () with the sulfonylurea glyburide has, in some patients, resulted in severe hypoglycemia. Fatalities have been reported.
The serum concentrations of Ciprofloxacin () and metronidazole were not altered when these two drugs were given concomitantly.
Quinolones, including Ciprofloxacin () , have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored.
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.
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.
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.
Following infusion of 400 mg I.V. Ciprofloxacin () every eight hours in combination with 50 mg/kg I.V. piperacillin sodium every four hours, mean serum Ciprofloxacin () concentrations were 3.02 mcg/mL 1/2 hour and 1.18 mcg/mL between 6–8 hours after the end of infusion.
Eight mutagenicity tests have been conducted with Ciprofloxacin () . Test results are listed below:
/Microsome Test (Negative) DNA Repair Assay (Negative) Mouse Lymphoma Cell Forward Mutation Assay (Positive) Chinese Hamster V79 Cell HGPRT Test (Negative) Syrian Hamster Embryo Cell Transformation Assay (Negative) Point Mutation Assay (Negative) Mitotic Crossover and Gene Conversion Assay (Negative) Rat Hepatocyte DNA Repair Assay (Positive)
Thus, two of the eight tests were positive, but results of the following three test systems gave negative results:
Rat Hepatocyte DNA Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice)
Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to Ciprofloxacin () at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m).
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 maximum recommended human dose based upon mg/m), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16–32 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 (approximately 0.7-times the highest recommended therapeutic dose based upon mg/m) revealed no evidence of impairment.
Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as Ciprofloxacin () . This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involves the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing Ciprofloxacin () . to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue Ciprofloxacin () . and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (See , and ).
In a retrospective analysis of 23 multiple-dose controlled clinical trials of Ciprofloxacin () encompassing over 3500 Ciprofloxacin () treated patients, 25% of patients were greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin () is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients. (See and .)
In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using Ciprofloxacin () injection 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 torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
Ciprofloxacin () Adverse Reactions
During clinical investigations with oral and parenteral Ciprofloxacin () , 49,038 patients received courses of the drug. Most of the adverse events reported were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment. Ciprofloxacin () was discontinued because of an adverse event in 1.8% of intravenously treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of Ciprofloxacin () therapy were nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).
In clinical trials the following events were reported, regardless of drug relationship, in greater than 1% of patients treated with intravenous Ciprofloxacin () : nausea, diarrhea, central nervous system disturbance, local I.V. site reactions, liver function tests abnormal, eosinophilia, headache, restlessness, and rash. Many of these events were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment. Local I.V. site reactions are more frequent if the infusion time is 30 minutes or less. These may appear as local skin reactions which resolve rapidly upon completion of the infusion. Subsequent intravenous administration is not contraindicated unless the reactions recur or worsen.
Additional medically important events, without regard to drug relationship or route of administration, that occurred in 1% or less of Ciprofloxacin () patients are listed below:
BODY AS A WHOLE:
abdominal pain/discomfort, foot pain, pain, pain in extremities
CARDIOVASCULAR:
Cardiovascular collapse, cardiopulmonary arrest, myocardial infarction, arrhythmia, tachycardia, palpitation, cerebral thrombosis, syncope, cardiac murmur, hypertension, hypotension, angina pectoris, atrial flutter, ventricular ectopy, (thrombo)- phlebitis, vasodilation, migraine
CENTRAL NERVOUS SYSTEM:
Convulsive seizures, paranoia, toxic psychosis, depression, dysphasia, phobia, depersonalization, manic reaction, unresponsiveness, ataxia, confusion, hallucinations, dizziness, lightheadedness, paresthesia, anxiety, tremor, insomnia, nightmares, weakness, drowsiness, irritability, malaise, lethargy, abnormal gait, grand mal convulsion, anorexia
GASTROINTESTINAL:
Ileus, jaundice, gastrointestinal bleeding, associated diarrhea, pseudomembranous colitis, pancreatitis, hepatic necrosis, intestinal perforation, dyspepsia, epigastric pain, constipation, constipation, oral ulceration, oral candidiasis, mouth dryness, anorexia, dysphagia, flatulence, hepatitis, painful oral mucosa
HEMIC/LYMPHATIC:
Agranulocytosis, prolongation of prothrombin time, lymphadenopathy, petechia
METABOLIC/NUTRITIONAL
Amylase increase, lipase increase
MUSCULOSKELETAL:
Arthralgia, jaw, arm or back pain, joint stiffness, neck and chest pain, achiness, flare up of gout, myasthenia gravis.
RENAL/UROGENITAL:
Renal failure, interstitial nephritis, nephritis, hemorrhagic cystitis, renal calculi, frequent urination, acidosis, urethral bleeding, polyuria, urinary retention, gynecomastia, candiduria, vaginitis, breast pain. Crystalluria, cylindruria, hematuria and albuminuria have also been reported.
RESPIRATORY:
Respiratory arrest, pulmonary embolism, dyspnea, laryngeal or pulmonary edema, respiratory distress, pleural effusion, hemoptysis, epistaxis, hiccough, bronchospasm
SKIN/HYPERSENSITIVITY:
Allergic reactions, anaphylactic reactions including life-threatening anaphylactic shock, erythema multiforme/Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, vasculitis, angioedema, edema of the lips, face, neck, conjunctivae, hands or lower extremities, purpura, fever, chills, flushing, pruritus, urticaria, cutaneous candidiasis, vesicles, increased perspiration, hyperpigmentation, erythema nodosum, thrombophlebitis, burning, paresthesia, erythema, swelling, photosensitivity/phototoxicity reaction (See .)
SPECIAL SENSES:
Decreased visual acuity, blurred vision, disturbed vision (flashing lights, change in color perception, overbrightness of lights, diplopia), eye pain, anosmia, hearing loss, tinnitus, nystagmus, chromatopsia, a bad taste
In several instances, nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be related to elevated serum levels of theophylline possibly as a result of drug interaction with Ciprofloxacin () .
In randomized, double-blind controlled clinical trials comparing Ciprofloxacin () (I.V. and I.V./P.O. sequential) with intravenous beta-lactam control antibiotics, the CNS adverse event profile of Ciprofloxacin () was comparable to that of the control drugs.
Ciprofloxacin () , administered I.V. and /or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335 Ciprofloxacin () - and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or treatment-emergent). These events were evaluated in a comprehensive fashion and included such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates of these events were 9.3% (31/335) in the Ciprofloxacin () -treated group versus 6.0 % (21/349) in comparator-treated patients. The majority of these events were mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the events. The events occurred more frequently in Ciprofloxacin () -treated patients than control patients, regardless of whether they received I.V. or oral therapy.
Ciprofloxacin () -treated patients were more likely to report more than one event and on more than one occasion compared to control patients. These events occurred in all age groups and the rates were consistently higher in the Ciprofloxacin () group compared to the control group. At the end of 1 year, the rate of these events reported at any time during that period was 13.7% (46/335) in the Ciprofloxacin () -treated group versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued Ciprofloxacin () for wrist pain that developed during treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from Ciprofloxacin () cannot be excluded. The patient recovered by 4 months without surgical intervention.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the Ciprofloxacin () group versus 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and within 6 weeks of treatment initiation were 41% (138/335) in the Ciprofloxacin () group versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of Ciprofloxacin () patients compared to 9% (31/349) of comparator patients. Serious adverse events were seen in 7.5% (25/335) of Ciprofloxacin () -treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was observed in 3% (10/335) of Ciprofloxacin () -treated patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of Ciprofloxacin () patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3.0%, rhinitis 3.0%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events reported in adults during clinical trials or post-marketing experience may also occur in pediatric patients.
The following adverse events have been reported from worldwide marketing experience with quinolones, including Ciprofloxacin () . Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anosmia, candiduria, cholesterol elevation (serum), confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure, (including fatal cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice, marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal) myalgia, myasthenia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum), photosensitivity/phototoxicity reaction, potassium elevation (serum), prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis (toxic), renal calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis (Lyell's Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See .)
Adverse events were also reported by persons who received Ciprofloxacin () for anthrax post-exposure prophylaxis following the anthrax bioterror attacks of October 2001 (See also ).
The most frequently reported changes in laboratory parameters with intravenous Ciprofloxacin () therapy, without regard to drug relationship are listed below:
Other changes occurring infrequently were: decreased leukocyte count, elevated atypical lymphocyte count, immature WBCs, elevated serum calcium, elevation of serum gamma-glutamyl transpeptidase (γ GT), decreased BUN, decreased uric acid, decreased total serum protein, decreased serum albumin, decreased serum potassium, elevated serum potassium, elevated serum cholesterol. Other changes occurring rarely during administration of Ciprofloxacin () were: elevation of serum amylase, decrease of blood glucose, pancytopenia, leukocytosis, elevated sedimentation rate, change in serum phenytoin, decreased prothrombin time, hemolytic anemia, and bleeding diathesis.
Ciprofloxacin () Overdosage
In the event of acute overdosage, the patient should be carefully observed and given supportive treatment, including monitoring of renal function. Adequate hydration must be maintained. Only a small amount of Ciprofloxacin () (
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at intravenous doses of Ciprofloxacin () between 125 and 300 mg/kg.
Ciprofloxacin ()
Ciprofloxacin () How Supplied
Ciprofloxacin () Injection is available as a clear, colorless to slightly yellowish solution. Ciprofloxacin () Injection is available in 200 mg and 400 mg strengths. The premixed solution is supplied in latex-free flexible containers as follows:
Ciprofloxacin () Animal Pharmacology
Ciprofloxacin () and other quinolones have been shown to cause arthropathy in immature animals of most species tested. (See .) Damage of weight bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg Ciprofloxacin () , given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral Ciprofloxacin () doses of 30 mg/kg and 90 mg/kg Ciprofloxacin () (approximately 1.3- and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study, removal of weight bearing from the joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with Ciprofloxacin () . This is primarily related to the reduced solubility of Ciprofloxacin () under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon mg/m). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration (approximately 0.2-times the highest recommended therapeutic dose based upon mg/m).
In dogs, Ciprofloxacin () administered at 3 and 10 mg/kg by rapid intravenous injection (15 sec.) produces pronounced hypotensive effects. These effects are considered to be related to histamine release because they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also produces hypotension, but the effect in this species is inconsistent and less pronounced. In mice, concomitant administration of nonsteroidal anti-inflammatory drugs, such as phenylbutazone and indomethacin, with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.
Ocular toxicity, seen with some related drugs, has not been observed in Ciprofloxacin () -treated animals.
Ciprofloxacin () Inhalational Anthrax – Additional Information
The mean serum concentrations of Ciprofloxacin () associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral and intravenous regimens. (See ) Ciprofloxacin () pharmacokinetics have been evaluated in various human populations.The mean peak serum concentration achieved at steady-state in human adults receiving 500 mg orally every 12 hours is 2.97 mcg/mL, and 4.56 mcg/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 mcg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3 mcg/mL and trough concentrations range from 0.09 to 0.26 mcg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6 mcg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of Ciprofloxacin () to pediatric patients are limited. (For additional information, see .) Ciprofloxacin () serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD (~5.5 × 10) spores (range 5–30 LD) of was conducted. The minimal inhibitory concentration (MIC) of Ciprofloxacin () for the anthrax strain used in this study was 0.08 mcg/mL. In the animals studied, mean serum concentrations of Ciprofloxacin () achieved at expected T (1 hour post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 mcg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 mcg/mL. Mortality due to anthrax for animals that received a 30-day regimen of oral Ciprofloxacin () beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one Ciprofloxacin () -treated animal that died of anthrax did so following the 30-day drug administration period.
More than 9300 persons were recommended to complete a minimum of 60 days of antibiotic prophylaxis against possible inhalational exposure to during 2001. Ciprofloxacin () was recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons were also given anthrax vaccine or were switched to alternative antibiotics. No one who received Ciprofloxacin () or other therapies as prophylactic treatment subsequently developed inhalational anthrax. The number of persons who received Ciprofloxacin () as all or part of their post-exposure prophylaxis regimen is unknown.
Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported receiving Ciprofloxacin () as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems sleeping, nightmares, headache, dizziness or lightheadedness) and musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more frequent than had been previously reported in controlled clinical trials. This higher incidence, in the absence of a control group, could be explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional stress or other confounding factors, and/or a longer treatment period with Ciprofloxacin () . Because of these factors and limitations in the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.
Ciprofloxacin () Clinical Studies
NOTE: Although effective in clinical trials, Ciprofloxacin () is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues.
Ciprofloxacin () , administered I.V. and/or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety.
Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria).
The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between Ciprofloxacin () and the comparator group as shown below.
Ciprofloxacin ()
Ciprofloxacin ()
Ciprofloxacin () Principal Display Panel - Mg Carton Label
100 mL Single Dose Flexible Plastic Container.
Sterile, Nonpyrogenic. Contains No Preservative.
Ciprofloxacin () Principal Display Panel - Mg Carton Label
200 mL Single Dose Flexible Plastic Container.
Sterile, Nonpyrogenic. Contains No Preservative.
