Cipro IV

It is very important that your doctor check your or your child's progress while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it. Blood and urine tests may be needed to check for unwanted effects.

Do not take tizanidine (Zanaflex®) while you are receiving this medicine. Tell your doctor if you or your child are also using theophylline (Theo-Dur®) or other products that contain caffeine (eg, coffee, soda, chocolate). Using these medicines together may increase risks for more serious side effects.

Ciprofloxacin may rarely cause inflammation (tendinitis) or tearing of a tendon (the cord that attaches muscles to bones). This can occur while you are using the medicine or after you finish using it. The risk of having tendon problems may be increased if you are over 60 years of age, are using steroid medicines (eg, dexamethasone, prednisolone, prednisone, Medrol®), have severe kidney problems, have a history of tendon problems (eg, rheumatoid arthritis), or if you have received an organ transplant (eg, heart, kidney, or lung). Check with your doctor right away if you have sudden pain or swelling in a tendon after exercise (eg, ankle, back of the knee or leg, shoulder, elbow, or wrist), bruise more easily after an injury, or are unable to bear weight or move the affected area. Refrain from exercise until your doctor says otherwise.

Tell your doctor right away if you or your child have any of the following symptoms while using this medicine: convulsions, feeling anxious, confused, or depressed, seeing, hearing, or feeling things that are not there, severe headache, trouble sleeping, or unusual thoughts or behaviors.

This medicine may cause serious allergic reactions, including anaphylaxis, which can be life-threatening and require immediate medical attention. Call your doctor right away if you or your child have a rash, itching, hives, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth after you receive this medicine.

Serious skin reactions can occur with this medicine. Check with your doctor right away if you or your child have blistering, peeling, or loose skin, red skin lesions, severe acne or skin rash, sores or ulcers on the skin, or fever or chills while you are using this medicine.

Check with your doctor right away if you or your child have dark urine, clay-colored stools, abdominal or stomach pain, or yellow eyes or skin. These maybe symptoms of a serious liver problem.

Ciprofloxacin injection may cause diarrhea, and in some cases it can be severe. It may occur 2 months or more after you stop using this medicine. Do not take any medicine to treat diarrhea without first checking with your doctor. Diarrhea medicines may make the diarrhea worse or make it last longer. If you have any questions about this or if mild diarrhea continues or gets worse, check with your doctor.

Tell your doctor right away if you or your child start having numbness, tingling, or burning pain in your hands, arms, legs, or feet. These may be symptoms of a condition called peripheral neuropathy.

Some people who receive ciprofloxacin injection may become more sensitive to sunlight than they are normally. Exposure to sunlight, even for brief periods of time, may cause severe sunburn, or skin rash, redness, itching, or discoloration. When you or your child begin receiving this medicine:

• Stay out of direct sunlight, especially between the hours of 10:00 AM and 3:00 PM, if possible.
• Wear protective clothing, including a hat and sunglasses.
• Apply a sun block product that has a sun protection factor (SPF) of at least 15. Some people may require a product with a higher SPF number, especially if they have a fair complexion. If you have any questions about this, check with your doctor.
• Do not use a sunlamp or tanning bed or booth.

If you have a severe reaction from the sun, check with your doctor.

Ciprofloxacin injection may cause some people to become dizzy, lightheaded, drowsy, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that can be dangerous if you are dizzy or not alert. If these reactions are especially bothersome, check with your doctor.

If you are a diabetic patient taking diabetes medicine by mouth: Ciprofloxacin may cause hypoglycemia (low blood sugar) in some patients. Symptoms of low blood sugar must be treated before they lead to unconsciousness (passing out). Different people may feel different symptoms of low blood sugar. If you or your child experience symptoms of low blood sugar, stop using ciprofloxacin and check with your doctor right away:

• Symptoms of low blood sugar can include: Anxious feeling, behavior change similar to being drunk, blurred vision, cold sweats, confusion, cool pale skin, difficulty with concentrating, drowsiness, excessive hunger, headache, nausea, nervousness, rapid heartbeat, shakiness, or unusual tiredness or weakness.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Injection (200 mL in 5% Dextrose, 400 mg, 0.2%) Premix in Flexible Containers, for intravenous infusion

Hypersensitivity

Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antibacterials, or any of the product components [see Warnings and Precautions (5.7)].

Tizanidine

Concomitant administration with tizanidine is contraindicated [see Drug Interactions (7)].

Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of Cipro IV with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug.

Mechanism of Action

Ciprofloxacin is a member of the fluoroquinolone class of antibacterial agents [see Microbiology (12.4)].

Pharmacokinetics

Following 60-minute intravenous infusions of 200 mg and 400 mg Cipro IV 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 (Table 9).

Table 9: Steady-state Ciprofloxacin Serum Concentrations (mcg/mL) After 60-minute INTRAVENOUS Infusions every 12 hours.

The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 mg to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th intravenous dose on an every 12 hour 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 intravenous dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg CIPRO given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours (Table 10).

After intravenous administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.

After intravenous administration, three metabolites of ciprofloxacin have been identified in human urine which together account for approximately 10% of the intravenous dose. The metabolites have antimicrobial activity, but are less active than unchanged. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the co-administered drug [see Contraindications (4.2), Warnings and Precautions (5.9, 5.15) and Drug Interactions (7)].

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 intravenous 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 intravenous 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 (<less than1%) is recovered from the bile as unchanged drug. Approximately 15% of an intravenous dose is recovered from the feces within 5 days after dosing.

Elderly

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 (older than 65 years) as compared to young adults. Although the Cmax is increased 16% to 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 Use in Specific Populations (8.5)].

Renal Impairment

In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required [see Use in Specific Populations (8.6) and Dosage and Administration (2.3)].

Hepatic Impairment

In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, have not been fully studied.

Pediatrics

Following a single oral dose of 10 mg/kg CIPRO suspension to 16 children ranging in age from 4 months to 7 years, the mean Cmax was 2.4 mcg/mL (range: 1.5 to 3.4 mcg/mL) and the mean AUC was 9.2 mcg*hr/mL (range: 5.8 mcg*hr/mL to 14.9 mcg*hr/mL). There was no apparent age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg three times a day). In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 mcg/mL (range: 4.6 mcg/mL to 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL (range: 4.7 mcg/mL to 11.8 mcg/mL) in 10 children between 1 year and 5 years of age. The AUC values were 17.4 mcg*hr/mL (range: 11.8 mcg*hr/mL to 32.0 mcg*hr/mL) and 16.5 mcg*hr/mL (range: 11 mcg*hr/mL to 23.8 mcg*hr/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 hours–5 hours, and the bioavailability of the oral suspension is approximately 60%.

Metronidazole

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

Tizanidine

In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with CIPRO (500 mg twice a day for 3 days). Concomitant administration of tizanidine and Cipro IV is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].

Ropinirole

In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole once daily with 500 mg CIPRO twice-daily, the mean Cmax and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with Cipro IV [see Warnings and Precautions (5.15)].

Clozapine

Following concomitant administration of 250 mg CIPRO with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with Cipro IV are advised.

Sildenafil

Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg CIPRO to healthy subjects, the mean Cmax and mean AUC of sildenafil were both increased approximately two-fold. Use sildenafil with caution when co-administered with CIPRO due to the expected two-fold increase in the exposure of sildenafil upon co-administration of Cipro IV.

Duloxetine

In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase in mean AUC and a 2.5-fold increase in mean Cmax of duloxetine.

Lidocaine

In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg ciprofloxacin twice daily resulted in an increase of lidocaine Cmax and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible interaction with Cipro IV and an increase in adverse reactions related to lidocaine may occur upon concomitant administration.

Agomelatine

In clinical studies, it was demonstrated that fluvoxamine, as a strong inhibitor of the CYP450 1A2 isoenzyme, markedly inhibits the metabolism of agomelatine resulting in a 60-fold increase of agomelatine exposure. Although no clinical data are available for a possible interaction with ciprofloxacin, a moderate inhibitor of CYP450 1A2, similar effects can be expected upon concomitant administration with CIPRO.

Microbiology

The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), 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. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6.

There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.

Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-positive bacteria

Bacillus anthracis

Enterococcus faecalis

Staphylococcus aureus (methicillin-susceptible isolates only)

Staphylococcus epidermidis (methicillin-susceptible isolates only)

Staphylococcus saprophyticus

Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative bacteria

Citrobacter koseri

Citrobacter freundii

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis

Morganella morganii

Proteus mirabilis

Proteus vulgaris

Providencia rettgeri

Providencia stuartii

Pseudomonas aeruginosa

Serratia marcescens

Yersinia pestis

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ciprofloxacin (≤1 mcg/mL). However, the efficacy of ciprofloxacin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

Staphylococcus haemolyticus (methicillin-susceptible isolates only)

Staphylococcus hominis (methicillin-susceptible isolates only)

Gram-negative bacteria

Acinetobacter lwoffi

Aeromonas hydrophila

Edwardsiella tarda

Enterobacter aerogenes

Klebsiella oxytoca

Legionella pneumophila

Pasteurella multocida

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar).5, 6, 7 The MIC values should be interpreted according to criteria provided in Table 11.

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.6, 7, 8 This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in Table 11.

A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.5, 6, 7, 8 Standard ciprofloxacin powder should provide the following range of MIC values noted in Table 12. For the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in Table 12 should be achieved.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Get emergency medical help if you have signs of an allergic reaction to ciprofloxacin: hives, or the first sign of a skin rash; fast heartbeat, difficult breathing; swelling of your face, lips, tongue, or throat.

Ciprofloxacin may cause your tendons to swell or cause tendon rupture. It can also have serious effects on your nerves, and may cause permanent nerve damage. Stop using this medicine and call your doctor at once if you have:

• signs of tendon rupture - sudden pain, swelling, bruising, tenderness, stiffness, movement problems, or a snapping or popping sound in any of your joints (rest the joint until you receive medical care or instructions); or

• nerve symptoms - numbness, tingling, burning pain, or being more sensitive to temperature, light touch, or the sense of your body position.

Also, stop using this medicine and call your doctor at once if you have:

• severe stomach pain, diarrhea that is watery or bloody;

• a headache with chest pain and severe dizziness and fast or pounding heartbeats;

• the first sign of any skin rash, no matter how mild;

• confusion, hallucinations, nightmares, paranoia, depression, thoughts about hurting yourself;

• muscle weakness or trouble breathing;

• ongoing headaches (sometimes with blurred vision);

• tremors, anxiety, trouble sleeping, feeling restless or nervous;

• a light-headed feeling, like you might pass out;

• increased pressure inside the skull - severe headaches, ringing in your ears, dizziness, vision problems, pain behind your eyes;

• liver problems - nausea, vomiting, loss of appetite, upper stomach pain, itching, fever, tiredness, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes); or

• severe skin reaction - fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common ciprofloxacin side effects may include:

• nausea, vomiting, diarrhea;

• rash; or

• abnormal liver function tests.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:

• Like other quinolones, ciprofloxacin is associated with an increased risk of tendinitis and tendon rupture at all ages. Seniors over 60, people taking corticosteroids or with a history of organ transplants are at increased risk.
• Not usually a drug of first choice for children as children are more susceptible to the adverse effects of ciprofloxacin.
• May exacerbate muscle weakness in people with myasthenia gravis.
• Serious, sometimes life-threatening, adverse reactions such as liver damage and allergic reactions have been occasionally reported.
• May trigger seizures or increase the risk of having a seizure.
• May also cause anxiety, insomnia, psychotic reactions, nausea, nerve pain or loss of feeling, ECG abnormalities, increase sensitivity to light and other effects.

Notes: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects. For a complete list of all side effects, click here.

• Take exactly as directed and for the duration intended.
• Only use when prescribed by a doctor to treat infections caused by susceptible bacteria as improper use increases the chance of resistant bacteria developing.
• Do not take ciprofloxacin within two hours of magnesium/aluminum-containing antacids or other products containing calcium, iron or zinc. Other products may also affect absorption (check product information).
• Avoid administration of ciprofloxacin with dairy products (eg, milk or yogurt) or calcium-fortified juices alone; however, ciprofloxacin may be taken with meals that contain calcium.
• Protect yourself from sunlight and avoid excessive exposure to the sun when taking ciprofloxacin.
• Keep well hydrated when taking ciprofloxacin to avoid the formation of highly concentrated urine.
• Discontinue if pain, swelling, inflammation or tendon rupture occurs and seek immediate medical advice.
• Discontinue immediately if a skin rash, yellowing of the skin, dark urine, itchiness, or allergy symptoms develop.
• Seek medical advice if chronic diarrhea develops during or following ciprofloxacin.

Peak concentrations are reached one to two hours after dosing; however it may take up to 48 hours before infection-related symptoms start to abate.

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