Pr
Ciprofloxacin Injection USP
2 mg ciprofloxacin/mL in 5% dextrose injection Sterile Antibacterial Agent Hospira Healthcare Corporation 1111 Dr. Frederik-Philips, Suite 600 St-Laurent, Quebec H4M 2X6 Date of Preparation: November 8, 2007 Submission Control No: 105935
Table of Contents
SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 9 DRUG INTERACTIONS 12 DOSAGE AND ADMINISTRATION 14 OVERDOSAGE 17 ACTION AND CLINICAL PHARMACOLOGY 17 STORAGE AND STABILITY 19 SPECIAL HANDLING INSTRUCTIONS 20 DOSAGE FORMS, COMPOSITION AND PACKAGING 20
PHARMACEUTICAL INFORMATION 21 DETAILED PHARMACOLOGY 21 MICROBIOLOGY 27 TOXICOLOGY 33 REFERENCES 36
PrCIPROFLOXACIN INJECTION USP 2 mg ciprofloxacin/mL in 5% dextrose injection Sterile
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Intravenous | 2 mg/mL in 5% Dextrose | none For a complete listing see Dosage Forms, Composition and Packaging section. |
CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) may be indicated for the treatment of patients with the following infections caused by susceptible strains of the indicated microorganisms:
Respiratory Tract Infections
Acute pneumonia caused by: Enterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Staphylococcus aureus Streptococcus pneumoniae Due to the nature of the underlying conditions which usually predispose patients to pseudomonas infections of the respiratory tract, bacterial eradications may not be achieved in patients who display clinical improvement despite evidence of in vitro sensitivity. In patients requiring subsequent courses of therapy, PrCIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) should be used alternately with other antipseudomonal agents. Some strains of Pseudomonas aeruginosa may develop resistance during treatment. Therefore, susceptibility testing should be performed periodically during therapy to detect the emergence of bacterial resistance.
Urinary Tract Infections
Upper and lower complicated urinary tract infections including pyelonephritis caused by:
Citrobacter diversus Escherichia coli Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa
Skin or Skin Structure Infections caused by:
Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Morganella morganii Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Staphylococcus aureus Streptococcus pyogenes
Septicemia Caused by: Escherichia coli Salmonella typhi
Bone
Caused by:
Enterobacter cloacae Pseudomonas aeruginosa
Complicated Intra-abdominal Infections only when used in Combination with Metronidazole (See DOSAGE AND ADMINISTRATION.) Caused by:
Escherichia coli Pseudomonas aeruginosa Klebsiella pneumoniae Bacteroides fragilis
Note: Most anaerobic bacteria, including Bacteroides fragilis, are resistant to ciprofloxacin. Therefore, ciprofloxacin should not be used as single agent therapy for complicated intra- abdominal infections. Efficacy against Enterococcus sp. in clinical trials has been shown to be only 75%.
Empiric Therapy in Febrile Neutropenic Patients (in Combination with Piperacillin Sodium) (See DOSAGE AND ADMINISTRATION.) Appropriate culture and susceptibility tests should be performed prior to initiating treatment in order to isolate and identify organisms causing the infection and to determine their susceptibilities to ciprofloxacin. Therapy with CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) may be initiated before results of these tests are known. However, modification of this treatment may be required once results become available or if there is no clinical improvement. Culture and susceptibility testing performed periodically during therapy will provide information on the possible emergence of bacterial resistance. If anaerobic organisms are suspected to be contributing to the infection, appropriate therapy should be administered.
Geriatrics:
Evidence from clinical studies suggests that use in the geriatric population may be associated with differences in safety. A brief discussion can be found in WARNINGS AND PRECAUTIONS and DETAILED PHARMACOLOGY, Human Pharmacokinetics.
Pediatrics (< 18 years of age):
The safety of ciprofloxacin in individuals less than 18 years of age has not been established. (See WARNINGS AND PRECAUTIONS.)
Pregnant Women and Nursing Women:
The safety of ciprofloxacin in pregnant women and nursing woman has not been established. (See WARNINGS AND PRECAUTIONS.)
CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) is contraindicated in patients who have shown hypersensitivity to ciprofloxacin or other quinolone antibacterial agents or any of the excipients. Concurrent administration of ciprofloxacin and tizanidine is contraindicated since it may result in an undesirable increase in serum tizanidine concentrations. This can be associated with clinically relevant tizanidine-induced side effects (hypotension, somnolence, drowsiness).
General
Intravenous infusion should be administered by slow infusion over a period of 60 minutes. Local I.V. reactions have been reported with the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30 minutes or less or if small veins of the hand are used. Prolonged use of CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is therefore essential, and if superinfection should occur during therapy, appropriate measures should be taken.
. These reactions include cardiac arrest, seizure, status epilepticus and respiratory failure. Similar serious adverse events have been noted with administration of theophylline alone; however, the possibility that ciprofloxacin may potentiate these reactions cannot be eliminated. If concomitant use cannot be avoided, the plasma levels of theophylline should be monitored and appropriate dosage adjustments should be made.
Endocrine and Metabolism
Ciprofloxacin is known to be a moderate inhibitor of the CYP450 1A2 enzymes. Care should be taken when other drugs are administered concomitantly which are metabolized via the same enzymatic pathway (e.g., theophylline, methylxantines, caffeine, duloxetine). Increased plasma concentrations associated with drug specific side effects may be observed due to inhibition of their metabolic clearance by ciprofloxacin. (See CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions).
Gastrointestinal
Pseudomembranous colitis has been reported with virtually all antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients with diarrhea subsequent to the administration of antibacterial agents. Subsequent to diagnosis of pseudomembranous colitis, therapeutic measures should be initiated. Mild cases will usually respond to discontinuation of drug alone. In moderate to severe cases, consideration should be given to the management with fluids, electrolytes, protein supplementation and treatment with an antibacterial drug effective against
C. difficile.
Genitourinary
Crystalluria related to ciprofloxacin has been reported only rarely in man because human urine is usually acidic. Crystals have been observed in the urine of laboratory animals, usually from alkaline urine. Patients receiving ciprofloxacin should be well hydrated and alkalinity of the urine should be avoided. The recommended daily dose should not be exceeded.
Hepatic/Biliary/Pancreatic
In preliminary studies in patients with stable chronic liver cirrhosis (with mild to moderate hepatic impairment), no significant changes in ciprofloxacin pharmacokinetics were observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency and stable chronic cirrhosis (with severe hepatic impairment), however, have not been fully elucidated. An increased incidence of nausea, vomiting, headache and diarrhea were observed in this patient population. (See DETAILED PHARMACOLOGY, Human Pharmacokinetics.)
Neurologic
Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, hallucinations, depression, nervousness, agitation, insomnia, anxiety, paranoia, nightmares and rarely, suicidal thoughts or acts. In rare cases, depression or psychosis can progress to self- endangering behaviour. These reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors that predispose to seizures or lower the seizure threshold. (See ADVERSE REACTIONS.)
Even when ciprofloxacin is taken exactly as prescribed, it can affect the speed of reaction to such an extent that the ability to drive or to operate machinery is impaired. This applies particularly in combination with alcohol.
Psychiatric
See Neurologic.
Renal
Since ciprofloxacin is eliminated primarily by the kidney, CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) should be used with caution and at a reduced dosage in patients with impaired renal function. (See DOSAGE AND ADMINISTRATION, DETAILED PHARMACOLOGY, Human Pharmacokinetics.)
Sensitivity/Resistance
Serious hypersensitivity and/or anaphylactic reactions have been reported in patients receiving quinolone therapy, including ciprofloxacin. These reactions may occur within the first 30 minutes following the first dose and may require epinephrine and other emergency measures. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock, seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath and acute respiratory distress), dyspnea, urticaria, itching and other serious skin reactions.
Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated. Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving therapy with all antibiotics. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following: fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson Syndrome), vasculitis, arthralgia, myalgia, serum sickness, allergic pneumonitis, interstitial nephritis, acute renal insufficiency or failure, hepatitis, jaundice, acute hepatic necrosis or failure, hepatic necrosis with fatal outcome, anemia including hemolytic and aplastic, thrombocytopenia including thrombotic thrombocytopenic purpura, leukopenia, agranulocytosis, pancytopenia, and/or other hematologic abnormalities. Resistance: Resistance to ciprofloxacin in vitro develops slowly via multiple-step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between <1x10-9 to 1x10-6.
Skin
Ciprofloxacin has been shown to produce photosensitivity reactions. Patients taking ciprofloxacin should avoid direct exposure to excessive sunlight or UV light. Therapy should be discontinued if photosensitization (i.e., sunburn-like skin reactions) occurs.
Special Populations
The safety of CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) has not been established. CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) should not be used in pregnant women unless the likely benefits outweigh the possible risk to the fetus. Ciprofloxacin has been shown to be non-embryotoxic and non- teratogenic in animal studies.
Ciprofloxacin is excreted in human milk. Because of the potential for serious adverse reactions in infants nursing from women taking ciprofloxacin, a decision should be made to discontinue nursing or to discontinue the administration of CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection), taking into account the importance of the drug to the mother and the possible risk to the infant.
The safety and efficacy of ciprofloxacin in individuals less than 18 years of age have not been established. Quinolones, including ciprofloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species. (See ADVERSE REACTIONS and TOXICOLOGY.)
Damage to juvenile weight-bearing joints and lameness were observed both in rat and dog studies but not in weaned piglets. Histopathological examination of the weight-bearing joints in immature dogs revealed permanent lesions of the cartilage. (See TOXICOLOGY.)
Tendon rupture (predominantly achilles tendon) has been reported predominantly in the elderly on prior systemic treatment with glucocorticoids. At any sign of tendonitis (i.e., painful swelling), the administration of ciprofloxacin should be discontinued, physical exercise avoided, and a physician consulted.
Ciprofloxacin is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. (See DETAILED PHARMACOLOGY, Human Pharmacokinetics.)
Adverse Drug Reaction Overview
CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) is generally well tolerated. The most frequent adverse events possibly, probably drug-related reported with use of ciprofloxacin injection include rash diarrhea and injection site pain. During worldwide clinical investigation, 16,580 courses of ciprofloxacin treatment (oral, I.V., and sequential therapy) were evaluated for drug safety.
Clinical Trial Adverse Drug Reactions
Adverse events, possibly, probably or highly probably related to ciprofloxacin occurred in 1,395 (8.8%) of patients. The adverse reactions according to treatment (oral, I.V., and sequential therapy) show that the incidence of adverse reactions was 8.0% for the group treated orally, 17% for the group treated with intravenous ciprofloxacin, and 15.3% for the group treated sequentially. The difference between the oral and I.V. group relates to adverse vascular reactions which are known to be associated with I.V. administration. In orally treated patients enrolled in clinical trials, the most frequently reported events, possibly, probably drug-related were: nausea (1.3%), and diarrhea (1.0%). In patients treated with ciprofloxacin I.V. the most frequently reported events, possibly, probably drug-related were: rash (1.8%), diarrhea (1.0%), and injection site pain (l.0%). Local I.V. site reactions have been reported. These 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 I.V. administration is not contraindicated unless the reactions recur or worsen.
Less Common Clinical Trial Adverse Drug Reactions (<1%)
(ciprofloxacin oral and I.V.)
Events possibly, probably drug-related occurring at a frequency of less than 1% with ciprofloxacin oral and i.v. treatment during clinical trials and subsequent post-marketing surveillance are as follows:
Body as a Whole:
back pain, chest pain, pain, pain in extremities, moniliasis.
Cardiovascular System: palpitation, phlebitis, (thrombo)-phlebitis (at infusion site), tachycardia. Rarely:hypotension. Very Rarely:angina pectoris, atrial fibrillation, cardiac arrest, cerebrovascular disorder, electrocardiogram abnormality, hot flashes, hypertension, kidney vasculitis, myocardial infarct, pericarditis, pulmonary embolus, substernal chest pain, syncope (fainting), vasodilation (hot flashes). Digestive: abdominal pain, anorexia, dry mouth, dyspepsia, dysphagia, enlarged abdomen, flatulence, gastrointestinal moniliasis, jaundice, stomatitis, vomiting, abnormal liver function test. Rarely:moniliasis (oral), cholestatic jaundice, and pseudomembranous colitis. Very Rarely:constipation, esophagitis, gastrointestinal hemorrhage, glossitis, hepatomegaly, ileus, increased appetite, intestinal perforation, life-threatening pseudomembranous colitis with possible fatal outcome, liver damage, melena, pancreatitis, tenesmus, tooth discoloration, toxic megacolon, ulcerative stomatitis.
Endocrine and Metabolism: PHARMACEUTICAL INFORMATION
The 5% dextrose w/v intravenous solution is unsuitable for patients with rare glucose-galactose malabsorption. (See
).
Hemic and Lymphatic: agranulocytosis, anaemia, eosinophilia, granulocytopenia, leukocytopenia, leukocytosis, pancytopenia. Very Rarely:altered prothrombin levels, haemolytic anaemia, marrow depression (life threatening), pancytopenia (life threatening), thrombocytopenia, thrombocytosis. Hypersensitivity: rash. Rarely:allergic reaction, anaphylactic/anaphylactoid reactions including facial, vascular and laryngeal edema, drug fever, haemorrhagic bullae and small nodules (papules) with crust formation showing vascular involvement (vasculitis), hepatitis, interstitial nephritis, petechiae (punctuate skin hemorrhages), pruritus, serum sickness-like reaction, Stevens-Johnson syndrome. Very Rarely:shock (anaphylactic; life-threatening), pruritic rash, erythema multiforme (minor), erythema nodosum, major liver disorders including hepatic necrosis, (very rarely progressing to life threatening hepatic failures), epidermal necrolysis (Lyell Syndrome). Infusion Site: thrombophlebitis, injection site reaction (e.g. edema/hypersensitivity/ inflammation/pain). Very Rarely:burning, erythema, pain, paresthesia, and swelling. Metabolic and Nutritional Disorder: creatinine increased. Rarely:edema (face) and hyperglycemia.
Musculoskeletal: Rarely:achiness, arthralgia (joint pain), joint disorder (joint swelling), pain in the extremities, partial or complete tendon rupture (predominantly achilles tendon), tendonitis (predominantly achillotendonitis), myalgia (muscular pain). Very Rarely:myasthenia (exacerbation of symptoms of myasthensia gravis). There have been 54 reports of arthropathies with ciprofloxacin. Ten of these reports involved children. Arthralgia was usually the first symptom which led to rapid assessment and withdrawal of the drug. No irreversible arthropathies have been observed. Nervous System: agitation, confusion, convulsion, dizziness, hallucinations, headache, hypesthesia, increased sweating, insomnia, somnolence, tremor (trembling). Rarely:paresthesia (peripheral paralgesia). Very Rarely:abnormal dreams (nightmares), anxiety, apathy, ataxia, depersonalization, depression, diplopia, hemiplegia, hyperesthesia, hypertonia, increase of intracranial pressure, meningism, migraine, nervousness, neuritis, paresthesia, polyneuritis, sleep disorder, twitching, grand mal convulsions, abnormal (unsteady) gait, psychosis, intracranial hypertension. In some instances these reactions occurred after the first administration of ciprofloxacin. In these instances, ciprofloxacin has to be discontinued and the doctor should be informed immediately.
Other: Rarely
: asthenia (general feeling of weakness, tiredness), death.
Respiratory System: dyspnea. Very Rarely:hiccup, hyperventilation, increased cough, larynx edema, lung edema, lung hemorrhage, pharyngitis, stridor, voice alteration. Skin/Appendages: pruritus, rash, maculopapular rash. Rarely:photosensitivity reaction. Very Rarely:alopecia, angioedema, fixed eruption, photosensitive dermatitis, petechia, urticaria. Special Senses: abnormal vision (visual disturbances), taste perversion, tinnitus. Rarely:transitory deafness (especially at higher frequencies), taste loss (impaired taste). Very Rarely:chromatopsia, colour blindness, conjunctivitis, corneal opacity, diplopia, ear pain, eye pain, parosmia (impaired smell), anosmia (usually reversible on discontinuation). Urogenital System: albuminuria, hematuria. Rarely:abnormal kidney function, acute kidney failure, dysuria, leukorrhea, nephritis interstitial, urinary retention, vaginitis, vaginal moniliasis. Most of the adverse events reported were described as only mild or moderate in severity. Adverse reactions noted during therapy with ciprofloxacin and metronidazole in clinical trials were similar to those already noted during therapy with ciprofloxacin alone with the following additions:
Cardiovascular:
peripheral edema
Digestive:
colitis, gastritis, tongue discoloration
Hemic and Lymphatic:
coagulation disorder, thrombocythemia
Skin: Metabolic: Nervous:
fungal dermatitis, pustular rash, sweating
healing abnormal, hypernatremia
dementia
Urinary:
kidney tumour necrosis, urinary incontinence
Abnormal Hematologic and Clinical Chemistry Findings
Increased alkaline phosphatase, ALT increased, AST increased, BUN (urea) increased, cholestatic parameters increased, Gamma - GT increased, lactic dehydrogenase increased, NPN increased, transaminases increased, decreased albuminuria, bilirubinemia, creatinine clearance decreased, hypercholesteremia, hyperuricemia, increased sedimentation rate. Rarely:acidosis, increased amylase, crystalluria, electrolyte abnormality, haematuria, hypercalcemia, hypocalcemia and lipase increased. The following additional adverse events, in alphabetical order, regardless of incidence or relationship to drug, have been reported during clinical trials and from worldwide post-marketing experience in patients given ciprofloxacin (includes all formulations, all dosages, all drug- therapy durations, and in all indications): arrhythmia, atrial flutter, bleeding diathesis, bronchospasm, C. difficile associated diarrhea, candiduria, cardiac murmur, cardiopulmonary arrest, cardiovascular collapse, cerebral thrombosis, chills, delirium, drowsiness, dysphasia, edema (conjunctivae, hands, lips, lower extremities, neck), epistaxis, exfoliative dermatitis, fever, gastrointestinal bleeding, gout (flare up), gynecomastia, hearing loss, hemoptysis, hemorrhagic cystitis, hyperpigmentation, joint stiffness, lightheadedness, lymphadenopathy, manic reaction, myoclonus, nystagmus, pain (arm, breast, epigastric, foot, jaw, neck, oral mucosa), paranoia, phobia, pleural effusion, polyuria, postural hypotension, pulmonary embolism, purpura, QT prolongation (frequency < 1 per million), renal calculi, respiratory arrest, respiratory distress, restlessness, rhabdomyolysis, torsades de pointes (frequency < 1 per million), toxic psychosis, unresponsiveness, urethral bleeding, urination (frequent), ventricular ectopy, ventricular fibrillation (frequency < 1 per million), ventricular tachycardia (frequency < 1 per million), vesicles, visual acuity (decreased) and visual disturbances (flashing lights, change in colour perception, overbrightness of lights).
Post-Market Adverse Drug Reactions
See Less Common Clinical Trial Adverse Drug Reactions summaries above.
.
These reactions include cardiac arrest, seizure, status epilepticus and respiratory failure. Similar serious adverse events have been noted with administration of theophylline alone; however, the possibility that ciprofloxacin may potentiate these reactions cannot be eliminated. If concomitant use cannot be avoided, the plasma levels of theophylline should be monitored and appropriate dosage adjustments should be made.
Overview
Clinically significant drug interactions occur with all fluoroquinolones. The drug interactions reported below are not exclusive to ciprofloxacin. Serum protein binding of ciprofloxacin is between 19 to 40%, and therefore significant protein binding interactions with other drugs is unlikely.
Drug-Drug Interactions
The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction.
Table 1: Established or Potential Drug-Drug Interactions
| Proper Name | Effect | Clinical Comment |
| theophylline | | serum theophylline; | elimination half-life. | Serious and fatal reactions have been reported. See Drug Interactions Box. If used concomitantly with ciprofloxacin, theophylline serum monitoring is recommended. |
| cyclosporin | Transient | serum creatinine | Observed with some quinolones, including ciprofloxacin. |
| warfarin | | effects of warfarin and warfarin derivatives | Reported with quinolones. During concomitant administration of ciprofloxacin and warfarin, prothrombin time or other appropriate coagulation tests should be closely monitored. |
| probenecid | | serum ciprofloxacin; blocks renal tubular secretion of ciprofloxacin | |
| glyburide | Action of glyburide intensified | |
| methotrexate | Inhibition of renal tubular transport of methotrexate; potential | plasma methotrexate | Increased risk of methotrexate associated toxic reactions. Patients receiving methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated. |
| Tizanidine | | C m ax : 7-fold; range: 4 to 21-fold | AUC: 10-fold, range: 6 to 24-fold | Associated with the increased serum concentrations was a potentiated hypotensive and sedative effect. Tizanidine must not be administered together with ciprofloxacin. |
| Duloxetine + Strong Inhibitors of CYP450 IA2 isozyme i.e. fluvoxamine | |AUC and C m ax of duloxetine | Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration. |
Concomitant administration of a nonsteroidal anti-inflammatory drug (fenbufen) with a quinolone (enoxacin) has been reported to increase the risk of CNS stimulation and convulsive seizures. Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.
Drug-Food Interactions
Caffeine has been shown to interfere with the metabolism and pharmacokinetics of ciprofloxacin. Excessive caffeine intake should be avoided.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.
Dosing Considerations
The determination of dosage for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative organism, the integrity of the patient's host-defense mechanisms, and the status of renal function.
Recommended Dose and Dosage Adjustment
Ciprofloxacin should be administered by I.V. infusion over a period of 60 minutes. Slow infusion into a large vein will minimize patient discomfort and reduce the risk of venous irritation.
The recommended adult dosages of CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) are:
Table 2: Recommended Adult Dosages of CIPROFLOXACIN INJECTION USP
| Location of Infection | Type/Severity | Unit Dose | Frequency | Daily Dose |
| Urinary Tract | Moderate/Severe/ Complicated | 200 mg to 400 mg | q12h | 400 mg to 800 mg |
| Respiratory Tract | Moderate/ Severe | 400 mg | q8h to q12h | 800 mg to 1200 mg |
| Skin or Skin Structure Blood | Moderate | 400 mg | q12h | 800 mg |
| Bone | ||||
| Intra-abdominal | Complicated | 400 mg | q12h | 400 mg q12h only when used in combination with metronidazole 500 mg I.V. q6h * |
| Empiric Therapy in Febrile Neutropenic Patients | Severe Ciprofloxacin + Piperacillin Sodium | 400 mg 50 mg/kg | q8h q4h | 1200 mg Not to exceed 24 g/day |
*1) Clinical success was demonstrated with a limited number of patients switched to oral therapy: (Ciprofloxacin 500 mg P.O. q12h plus metronidazole 500 mg P.O. q6h) during day 3, 4 or 5 of therapy when able to take oral medication and having shown an initial clinical response to the intravenous therapy.
See Metronidazole Product Monograph for Prescribing Information including cautionary statements.
For information on ciprofloxacin plus metronidazole combination therapy, see ACTION AND CLINICAL PHARMACOLOGY, DETAILED PHARMACOLOGOY, Human Pharmacokinetics, and ADVERSE REACTIONS sections of the Ciprofloxacin Product Monograph.
The duration of treatment depends upon the severity of infection. Generally ciprofloxacin should be continued for at least 3 days after the signs and symptoms of infection have disappeared. The usual duration is 7 to 14 days. However for severe and complicated infections more prolonged therapy may be required. Bone and joint infections may require treatment for 4 to 6 weeks or longer.
Sequential I.V./P.O. Therapy
In patients receiving intravenous ciprofloxacin, oral ciprofloxacin may be considered when clinically indicated at the discretion of the physician. However, clinical studies evaluating the use of sequential I.V./P.O. therapy in septicemia have not been completed.
Impaired Renal Function
Ciprofloxacin is eliminated primarily by renal excretion. However, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. (See DETAILED PHARMACOLOGY, Human Pharmacokinetics.) This alternate pathway of drug elimination appears to compensate for the reduced renal excretion of patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction. The following table provides a guideline for dosage adjustment. However, monitoring of serum drug levels provides the most reliable basis for dosage adjustments.
Table 3: Maximum Daily Dose with Stated Creatinine Clearance or Serum Creatinine
| Creatinine Clearance mL/min/1.73m 2 | Maximum Daily Dose | Serum Creatinine Concentration mg/100mL |
| I.V. | ||
| 31-60 | 800 mg | 1.4-1.9 |
| <= 30 | 400 mg | >= 2.0 |
Maximum daily dose, not to be exceeded when either creatinine clearance or serum creatinine are in the ranges stated.
Hemodialysis
Only a small amount of ciprofloxacin (< l0%) is removed from the body after hemodialysis or peritoneal dialysis. For hemodialysis patients, please follow dosing recommendations as described in Table 3. On dialysis days, the dose should be administered after dialysis. When only the serum creatinine concentration is available, the following formula (based on sex, weight and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function: Creatinine Clearance mL/sec = Males: Weight (kg) x (140 - age) 49 x serum creatinine (umol/L) Females: 0.85 x the above value In traditional units mL/min = Males: Weight (kg) x (140 - age) 72 x serum creatinine (mg/100 mL) Females: 0.85 x the above value
Impaired Hepatic Function
No dosage adjustment is required.
Pediatric Use
The safety and efficacy of ciprofloxacin in individuals less than 18 years of age has not been established. CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) should not be used in pediatric patients and adolescents. (See WARNINGS AND PRECAUTIONS.)
Missed Dose
No data is available.
Administration
CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) should be administered only by intravenous infusion over a period of 60 minutes. The drug should not be given by rapid injection. Slow infusion of a dilute solution into a large vein will minimize patient discomfort and reduce the risk of venous irritation. If CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each drug. CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) contains ciprofloxacin at 2.0 mg/mL in 5% dextrose and should be administered "as is".
Not Applicable. CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) is to be administered as is.
In the event of acute, excessive oral overdosage, reversible renal toxicity, arthralgia, myalgia and CNS symptoms have been reported. Therefore, apart from routine emergency measures, it is recommended to monitor renal function and to administer magnesium- or calcium-containing antacids which reduce the absorption of ciprofloxacin and to maintain adequate hydration. Based on information obtained from subjects with chronic renal failure, only a small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal dialysis.
Mechanism of Action
Ciprofloxacin, a synthetic fluoroquinolone, has in vitro activity against a wide range of gram- negative and gram-positive microorganisms. Its bactericidal action is achieved through inhibition of topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination. Ciprofloxacin retained some of its bactericidal activity after inhibition of RNA and protein synthesis by rifampin and chloramphenicol, respectively. These observations suggest ciprofloxacin may possess two bactericidal mechanisms, one mechanism resulting from the inhibition of DNA gyrase and a second mechanism which may be independent of RNA and protein synthesis. 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. Conversely, microorganisms resistant to fluoroquinolones may be susceptible to these other classes of antimicrobial agents. (See MICROBIOLOGY.) There is no cross-resistance between ciprofloxacin and the mentioned classes of antibiotics.
Pharmacodynamics
No data is available.
Pharmacokinetics
Table 4: Summary of Ciprofloxacin Injection Pharmacokinetic Parameters in Healthy Volunteers
| C max (mg/L) | t 1/2 (h) | AUC 0 - 4 (mg C h/L) | t max (h) | |
| 200 mg I.V. | 2.14 | 3.4 | 5.24 | 0.95 |
| 400 mg I.V. | 4.60 | 3.5 | 11.69 | 1.00 |
Following an intravenous infusion of ciprofloxacin the mean maximum serum concentrations were achieved at the end of infusion. Pharmacokinetics of ciprofloxacin were linear over the dose range up to 400 mg administered intravenously.
Comparison of the pharmacokinetic parameters for a bid and tid I.V. dose regimen indicated no evidence of drug accumulation for ciprofloxacin and its metabolites. A 60-minute I.V. infusion of 200 mg ciprofloxacin or the oral administration of 250 mg ciprofloxacin both given every 12 hours produced an equivalent area under the serum concentration time curve (AUC). A 60-minute infusion of 400 mg ciprofloxacin every 12 hours was bioequivalent to a 500 mg oral dose every 12 hours with regard to AUC. The 400 mg i.v. dose administered over 60 minutes every 12 hours resulted in a Cmax similar to that observed with a 750 mg oral dose. A 60-minute infusion of 400 mg ciprofloxacin every 8 hours is equivalent with respect to AUC to 750 mg oral regimen given every 12 hours.
The protein binding of ciprofloxacin is low (20-30%), and the substance is present in plasma largely in a non-ionized form. Ciprofloxacin can diffuse freely into the extravascular space. The large steady-state volume of distribution of 2-3 L/kg body weight shows that ciprofloxacin penetrates in tissues resulting in concentrations which clearly exceed the corresponding serum levels.
Metabolism: Small concentrations of four metabolites have been reported. They were identified as desethyleneciprofloxacin (M1), sulphociprofloxacin (M2), oxociprofloxacin (M3) and formylciprofloxacin (M4). M1 to M3 display antibacterial activity comparable to or inferior to that of nalidixic acid. M4, with the smallest quantity, is largely equivalent to norfloxacin in its antimicrobial activity.
Ciprofloxacin is largely excreted unchanged both renally and to a smaller extent non-renally. Renal clearance is between 0.18-0.3 L/h/kg and the total body clearance between 0.48-0.60 L/h/kg. Ciprofloxacin undergoes both glomerular filtration and tubular secretion. Non-renal clearance of ciprofloxacin is mainly due to active transintestinal secretion as well as metabolization. 1% of the dose is excreted via the biliary route. Ciprofloxacin is present in the bile in high concentrations.
Ciprofloxacin and metronidazole have been studied in combination and serum levels of ciprofloxacin are not significantly altered by metronidazole at the doses studied. Serum levels
of metronidazole when administered orally at a dose of 500 mg q6h in combination with ciprofloxacin 500 mg P.O. q12h are: AUC0-6 156.3 mg.h/L, Cmax 31.3 mg/L and tmax 1.71 hours. Serum levels of metronidazole when administered intravenously at a dose of 500 mg I.V. q6h in combination with ciprofloxacin 400 mg I.V. q12h are: AUC 0-6 153.0 mg.h/L, Cmax 33.6 mg/L and tmax 1.0 hours. (See DOSAGE AND ADMINISTRATION and DETAILED PHARMACOLOGY.) Following infusion of 400 mg I.V. Ciprofloxacin every eight hours in combination with 50 mg/kg I.V. piperacillin sodium every 4 hours, mean serum ciprofloxacin concentrations were 3.02 ug/mL at 30 minutes and 1.18 ug/mL between 6-8 hours after the end of infusion. The mean serum ciprofloxacin concentration given alone at 400 mg I.V. every eight hours was 3.67 ug/mL at 30 minutes and 1.16 ug/mL at 6 hours after the end of infusion.
Special Populations and Conditions
The safety and efficacy of CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) in individuals less than 18 years of age has not been established. CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) should not be used in pediatric patients and adolescents. (See WARNINGS AND PRECAUTIONS.)
See Renal Insufficiency.
No data is available.
No data is available.
No significant changes in ciprofloxacin pharmacokinetics were observed in studies in patients with stable chronic liver cirrhosis. (See WARNINGS AND PRECAUTIONS.)
Significantly increased concentrations of ciprofloxacin, M1 and M2 metabolites, and decreased renal clearances were observed in patients with renal insufficiency. Ciprofloxacin is excreted by the kidney, therefore, the risk of adverse reactions may be greater in patients with impaired renal function. (See DETAILED PHARMACOLOGY, Human Pharmacokinetics.)
No data is available.
CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) contains ciprofloxacin 2.0 mg/mL in 5% dextrose, and should be administered "as is". Protect from light, excessive heat and freezing. Store at controlled room temperature (20deg to 25degC). Use promptly when container is opened. Single use, discard unused portion. As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit.
See STORAGE AND STABILITY.
CIPROFLOXACIN INJECTION USP contains 2 mg ciprofloxacin per mL in 5% dextrose injection. Nonmedicinal ingredients include dextrose, lactic acid, hydrochloric acid, nitrogen, and water for injection. pH 3.5 to 4.6. CIPROFLOXACIN INJECTION USP (2mg/mL in 5% dextrose injection) is available in ready- to-use PVC flexible plastic containers with laminated foil overwrap of 100 mL and 200 mL.