Ciprofloxacin hydrochloride

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Ciprofloxacin hydrochloride

Overview

What is Ciprofloxacin hydrochloride?

Ciprofloxacin hydrochloride USP is a synthetic broad-spectrum antimicrobial agent for oral administration. Ciprofloxacin hydrochloride USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow crystalline substance that has the following chemical structure:

C HFNO•HCl•HO M.W. 385.8

Each Ciprofloxacin Tablet USP, for oral administration, is available in 250 mg, 500 mg or 750 mg strengths. In addition, each tablet also contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch, sodium starch glycolate, talc, titanium dioxide and triacetin.

What does Ciprofloxacin hydrochloride look like?

What are the available doses of Ciprofloxacin hydrochloride?

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What should I talk to my health care provider before I take Ciprofloxacin hydrochloride?

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How should I use Ciprofloxacin hydrochloride?

Ciprofloxacin Tablets USP are indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions and patient populations listed below. Please see for specific recommendations.

Ciproflaxacin tablets should be administered orally as described in the Dosage Guidelines table. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed (see and ).

Dosing and initial route of therapy (i.e., I.V. or oral) for complicated urinary tract infection or pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.

* The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days).

** Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus anthracis spores.

This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to predict clinical benefit. For a discussion of ciprofloxacin serum concentrations in various human populations, see

Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of complicated urinary tract infection and pyelonephritis. No information is available on dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine clearance of < 50 mL/min/1.73m).

What interacts with Ciprofloxacin hydrochloride?

Concomitant administration with tizanidine is contraindicated (see , ).

What are the warnings of Ciprofloxacin hydrochloride?

Tendinopathy and Tendon Rupture

Fluoroquinolones, including ciprofloxacin, 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. Ciprofloxacin 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.

Pregnant Women

THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED

PRECAUTIONS

Pregnancy

Nursing Mothers

Pediatrics

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 ).

Cytochrome P450 (CYP450)

Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of ciprofloxacin and other drugs primarily metabolized by the CYP1A2 (e.g., theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug.

Central Nervous System Disorders

Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS disorders 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 , , and ).

Theophylline

SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND THEOPHYLLINE.

Hypersensitivity Reactions

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. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as 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:

• fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome);

• vasculitis; arthralgia; myalgia; serum sickness;

• allergic pneumonitis;

• interstitial nephritis; acute renal insufficiency or failure;

• hepatitis; jaundice; acute hepatic necrosis or failure;

• anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic 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 and ).

Pseudomembranous Colitis

Clostridium difficile

C. difficile.

C. difficile

C. difficile

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.

Peripheral Neuropathy

Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving 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.

Syphilis

Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis after three months.

What are the precautions of Ciprofloxacin hydrochloride?

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 ). 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.

Central Nervous System

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

Renal Impairment

Alteration of the dosage regimen is necessary for patients with impairment of renal function (see ).

Photosensitivity/Phototoxicity

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 ).

As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy.

Prescribing ciprofloxacin 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:

Drug Interactions

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 a prolongation of its serum half-life.

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 decrease its absorption, resulting in serum and urine levels considerably lower than desired (see for concurrent administration of these agents with ciprofloxacin).

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

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, on rare occasions, resulted in severe hypoglycemia.

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

Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Eight mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below:

-Salmonella/Microsome Test (Negative)

- DNA Repair Assay (Negative)

-Mouse Lymphoma Cell Forward Mutation Assay (Positive)

-Chinese Hamster V 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, 2 of the 8 tests were positive, but results of the following 3 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 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 (approximately 0.7-times the highest recommended therapeutic dose based upon mg/m ) revealed no evidence of impairment.

Pregnancy

Nursing Mothers

Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential for serious adverse reactions 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

Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in weight-bearing joints of juvenile animals resulting in lameness (see ).

Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For information regarding pediatric dosing in inhalational anthrax (post-exposure), see and

Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis due to 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 the controls, including events related to joints and/or surrounding tissues. The rates of these events in pediatric patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6% (21/349) for control agents. The rates of these events occurring at any time up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31% (109/349) in the control arm (see and ).

Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5 to 17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10 to 21 days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10 to 21 days. Patients less than 5 years of age were not studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0 to 93 days). This study was not designed to determine long-term effects and the safety of repeated exposure to ciprofloxacin.

Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other adverse events were similar in nature and frequency between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days after a ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight months after treatment. However, the relationship of this event to the patient’s course of ciprofloxacin can not be definitively determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease process.

Geriatric Use

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as ciprofloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing ciprofloxacin to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue ciprofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (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 tablets 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).

What are the side effects of Ciprofloxacin hydrochloride?

Adverse Reactions in Adult Patients

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% of orally 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%), and rash (1%).

Additional medically important events that occurred in less than 1% of ciprofloxacin patients are listed below.

Body as a Whole:

Cardiovascular:

Central Nervous System:

Gastrointestinal:

Hemic/Lymphatic:

Metabolic/Nutritional:

Musculoskeletal:

Renal/Urogenital:

Respiratory:

Skin/Hypersensitivity:

Special Senses:

In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to cefuroxime axetil (250 mg to 500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the control drugs.

Adverse Reactions in Pediatric Patients

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% (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 study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed that of the control group by more than + 6%. At both the 6 week and 1 year evaluations, the 95% confidence interval indicated that it could not be concluded that ciprofloxacin group had findings comparable to the control group.

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%, rhinitis 3%, 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 postmarketing experience may also occur in pediatric patients.

	Ciprofloxacin	Comparator
All Patients (within 6 weeks)	31/335 (9.3%)	21/349 (6%)
95% Confidence Interval*	(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months	1/36 (2.8%)	0/41
≥ 2 years < 6 years	5/124 (4%)	3/118 (2.5%)
≥ 6 years < 12 years	18/143 (12.6%)	12/153 (7.8%)
≥ 12 years to 17 years	7/32 (21.9%)	6/37 (16.2 %)
All Patients (within 1 year)	46/335 (13.7%)	33/349 (9.5%)
95% Confidence Interval*	(-0.6%, + 9.1%)

Postmarketing Adverse Events

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, anaphylactic reactions (including life-threatening anaphylactic shock), 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 ).

Adverse Laboratory Changes

Changes in laboratory parameters listed as adverse events without regard to drug relationship are listed below:

Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, leukocytosis.

Hepatic	Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase (0.8%), LDH (0.4%), serum bilirubin (0.3%).
Hematologic	Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%), elevated blood platelets (0.1%), pancytopenia (0.1%).
Renal	Elevations of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA, CYLINDRURIA, AND HEMATURIA HAVE BEEN REPORTED.

What should I look out for while using Ciprofloxacin hydrochloride?

What might happen if I take too much Ciprofloxacin hydrochloride?

In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given supportive treatment, including monitoring of renal function and administration of magnesium, aluminum or calcium containing antacids which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal dialysis.

Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats, and dogs. No deaths occurred within a 14-day post treatment observation period at the highest oral doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical signs observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was delayed in these animals, occurring 10 to 14 days after dosing.

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.

How should I store and handle Ciprofloxacin hydrochloride?

Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5311” on one side and "250" on the other side containing ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5312” on one side and "500" on the other side containing ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin, packaged in bottles of 20, 100 and 500 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5313” on one side and "750" on the other side containing ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5311” on one side and "250" on the other side containing ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5312” on one side and "500" on the other side containing ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin, packaged in bottles of 20, 100 and 500 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5313” on one side and "750" on the other side containing ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5311” on one side and "250" on the other side containing ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5312” on one side and "500" on the other side containing ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin, packaged in bottles of 20, 100 and 500 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5313” on one side and "750" on the other side containing ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5311” on one side and "250" on the other side containing ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5312” on one side and "500" on the other side containing ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin, packaged in bottles of 20, 100 and 500 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5313” on one side and "750" on the other side containing ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5311” on one side and "250" on the other side containing ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5312” on one side and "500" on the other side containing ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin, packaged in bottles of 20, 100 and 500 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5313” on one side and "750" on the other side containing ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5311” on one side and "250" on the other side containing ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5312” on one side and "500" on the other side containing ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin, packaged in bottles of 20, 100 and 500 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5313” on one side and "750" on the other side containing ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5311” on one side and "250" on the other side containing ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5312” on one side and "500" on the other side containing ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin, packaged in bottles of 20, 100 and 500 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5313” on one side and "750" on the other side containing ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5311” on one side and "250" on the other side containing ciprofloxacin hydrochloride equivalent to 250 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5312” on one side and "500" on the other side containing ciprofloxacin hydrochloride equivalent to 500 mg ciprofloxacin, packaged in bottles of 20, 100 and 500 tablets and unit-dose boxes of 100 tablets.Ciprofloxacin Tablets USP are available as white to off-white, oval-shaped, unscored, film-coated tablets, debossedand “5313” on one side and "750" on the other side containing ciprofloxacin hydrochloride equivalent to 750 mg ciprofloxacin, packaged in bottles of 100 tablets and unit-dose boxes of 100 tablets.PHARMACIST: Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Clinical Information

Chemical Structure

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Clinical Pharmacology

Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are shown in the chart for the 250 mg to 1000 mg dose range.

Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg.

A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a C similar to that observed with a 400 mg I.V. dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg ciprofloxacin given every 12 hours.

Non-Clinical Toxicology

Ciprofloxacin hydrochloride 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 , ).

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 a prolongation of its serum half-life.

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 decrease its absorption, resulting in serum and urine levels considerably lower than desired (see for concurrent administration of these agents with ciprofloxacin).

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

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, on rare occasions, resulted in severe hypoglycemia.

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

Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin.

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.

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 ). 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.

Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Professional

Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

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