ciprofloxacin (Rx)

1-10%

Nausea (3%)

Abdominal pain (2%)

Diarrhea (2% adults; 5% children)

Increased aminotransferase levels (2%)

Vomiting (1% adults; 5% children)

Headache (1%)

Increased serum creatinine (1%)

Rash (2%)

Restlessness (1%)

<1%

Acidosis

Allergic reaction

Angina pectoris

Anorexia

Arthralgia

Ataxia

Back pain

Bad taste

Blurred vision

Breast pain

Bronchospasm

Diplopia

Dizziness

Drowsiness

Dysphagia

Dyspnea

Flushing

Foot pain

Hallucinations

Hiccups

Hypertension

Hypotension

Insomnia

Irritability

Joint stiffness

Lethargy

Migraine

Nephritis

Nightmares

Oral candidiasis

Palpitation

Photosensitivity

Polyuria

Syncope

Tachycardia

Tinnitus

Tremor

Urinary retention

Vaginitis

Postmarketing Reports

Acute generalized exanthematous pustulosis (AGEP), erythema multiforme, exfoliative dermatitis, fixed eruption, photosensitivity/phototoxicity reaction

Agitation, confusion, delirium

Agranulocytosis, albuminuria, serum cholesterol and TG elevations, blood glucose disturbances, hemolytic anemia, marrow depression (life threatening), pancytopenia (life threatening or fatal outcome), potassium elevation (serum)

Anaphylactic reactions (including life-threatening anaphylactic shock), serum sickness like reaction, Stevens-Johnson syndrome

Anosmia, hypesthesia

Constipation, dyspepsia, dysphagia, flatulence, hepatic failure (including fatal cases), hepatic necrosis, jaundice, pancreatitis

Hypertonia, hypotension (postural), increased INR (in patients treated with Vitamin K antagonists), QT prolongation, torsade de pointes, ventricular arrhythmia

Methemoglobinemia

Myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, peripheral neuropathy that may be irreversible, phenytoin alteration (serum), polyneuropathy, psychosis

Myalgia, tendinitis, tendon rupture, toxic epidermal necrolysis (Lyell’s Syndrome), twitching

Infections: Candiduria, vaginal candidiasis, moniliasis (oral, gastrointestinal, vaginal), pseudomembranous colitis

Renal calculi

Vasculitis

Aortic aneurysm and dissection

Contraindications

Documented hypersensitivity; concurrent tizanidine administration

Cautions

Use in pregnancy, though generally contraindicated for all quinolones, is allowed for life-threatening situations; limited data from use of ciprofloxacin in pregnancy show no higher rate of birth defects than background

Do not use oral suspension in nasogastric tube; to prepare, add microcapsules to diluent

Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion); these reactions can occur within hours to weeks after starting therapy, including in patients of any age or without pre-existing risk factors; discontinue therapy immediately at first signs or symptoms of any serious adverse reaction; in addition, avoid use of fluoroquinolones, in patients who have experienced any serious adverse reactions associated with fluoroquinolones (see Black Box Warnings)

Peripheral neuropathy: sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias, and weakness reported; peripheral neuropathy may occur rapidly after initiating and may potentially become permanent

In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal impairment; superinfections may occur with prolonged or repeated antibiotic therapy; discontinue use immediately if signs and symptoms of hepatitis occur

Not first drug of choice in pediatrics (except in anthrax), because of increased incidence of adverse events in comparison with control subjects, including arthropathy; no data exist on dosing for pediatric patients with renal impairment (ie, CrCl <50 mL/min)

Crystalluria may occur; urine alkalinity may increase risk; ensure adequate hydration during therapy

Serious and sometimes fatal hypoglycemia reported with fluoroquinolone use; hyperglycemia also reported; monitor patients closely for signs/symptoms of abnormal glucose levels; if hypoglycemic reaction occurs in a patient being treated discontinue therapy and initiate appropriate treatment immediately

Moderate-to-severe phototoxicity reactions reported; avoid excessive sunlight and take precautions to limit exposure; discontinue use if phototoxicity occurs

Acute onset of retinal detachment increased 4.5-fold with oral fluoroquinolones in a single case-controlled study - JAMA 2012;307(13):1414-1419; another study disputes these findings (relative risk, 1.29) - JAMA 2013;310(20):2184-2190

Clostridium difficile-associated diarrhea (CDAD) reported; if CDAD suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued; appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated

Prescribing antibiotics in absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to patient and increases risk of development of drug-resistant bacteria

Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis; postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis; avoid in patients with known history of myasthenia gravis

CNS effects

• Fluoroquinolones are associated with an increased risk of CNS effects(eg, convulsions, increased intracranial pressure [including pseudotumor cerebri], and toxic psychosis)
• May also cause CNS events including: nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and psychotic reactions have progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed suicide; reactions may occur following the first dose; advise patients to inform their healthcare provider immediately if these reactions occur, discontinue treatment, and institute appropriate care
• Fluoroquinolone are also known to trigger seizures or lower the seizure threshold; exercise caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (eg, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (eg, certain drug therapy, renal dysfunction)
• Cases of status epilepticus have been reported; if seizures occur, discontinue treatment

FDA MedWatch Safety Alert

• Issued 12-20-2018
• Increase in rate of aortic aneurysm and dissection reported within two months following use of fluoroquinolones, particularly in elderly patients
• May occur with fluoroquinolones for systemic use (IV or PO)
• Patients who have an aortic aneurysm or are at risk for an aortic aneurysm (eg, patients with peripheral atherosclerotic vascular diseases, hypertension, certain genetic conditions [eg, Marfan syndrome, Ehlers-Danlos syndrome], elderly patients)
• Prescribe fluoroquinolones to these patients only when no other treatment options are available
• Advise patients to seek immediate medical treatment for any symptoms associated with aortic aneurysm
• Stop treatment immediately if a patient reports side effects suggestive of aortic aneurysm or dissection

FDA MedWatch Safety Alert

• Issued July 10, 2018
• The FDA is strengthening the current warnings in the prescribing information for fluoroquinolone antibiotics to inform clinicians of significant decreases in blood glucose and certain mental health adverse effects
• Hypoglycemia, sometimes resulting in coma, occurred more frequently in elderly patients or in diabetic patients taking oral hypoglycemic medicine or insulin
• Alert patients regarding hypoglycemic symptoms and carefully monitor blood glucose levels; instruct patients how to treat themselves if symptoms of hypoglycemia occur
• This safety alert affects only systemic formulations; early signs and symptoms of low blood glucose include confusion, dizziness, feeling shaky, unusual hunger, headaches, irritability, pounding heart or very fast pulse, pale skin, sweating, trembling, weakness, and/or unusual anxiety
• Mental health side effects are to be added to or updated across all the fluoroquinolones are disturbances in attention, disorientation, agitation, nervousness, memory impairment, and delirium
• Inform patients of the potential risk of psychiatric adverse reactions that can occur after just 1 dose
• Immediately discontinue treatment if CNS adverse effects occur, including psychiatric adverse reactions, or blood glucose disturbances occur and switch to a nonfluoroquinolone antibiotic if possible

Drug interactions overview

• Serious and fatal reactions have reported in patients receiving concurrent administration of ciprofloxacin and theophylline; if concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate
• Coadministration of IV ciprofloxacin and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine, and zolpidem) results in increased plasma concentrations of co-administered drug and could lead to clinically significant pharmacodynamic adverse reactions of the co-administered drug
• Use with caution in patients with history of seizures taking concurrent therapy that lowers seizure threshold; risk increases rarely when administered concomitantly with NSAIDs
• Avoid IV administration in patients who have known QT prolongation, carry risk factors for prolonged QT, or are taking class 1A or class III antiarrhythmic drugs

Pregnancy

Prolonged experience with ciprofloxacin in pregnant women over several decades, based on available published information from case reports, case control studies and observational studies during pregnancy, have not identified any drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes

Oral administration during organogenesis at doses up to 100 mg/kg to pregnant mice and rats, and up to 30 mg/kg to pregnant rabbits did not cause fetal malformations; these doses were up to 0.3, 0.6, and 0.4 times the maximum recommended clinical oral dose in mice, rats, and rabbits, respectively, based on body surface area

Lactation

Published literature reports that ciprofloxacin is present in human milk following intravenous and oral administration; there is no information regarding effects on milk production or breastfed infant; because of potential risk of serious adverse reactions in breastfed infants, including arthropathy shown in juvenile animal studies

For most indications a lactating woman may consider pumping and discarding breast milk during treatment and an additional two days (five half-lives) after last dose; alternatively, advise a woman that breastfeeding is not recommended during treatment and for an additional two days (five half-lives) after last dose

However, for inhalation anthrax (post exposure), during an incident resulting in exposure to anthrax, the risk-benefit assessment of continuing breastfeeding while the mother (and potentially the infant) is (are) on CIPRO may be acceptable

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal condition

Ciprofloxacin may cause intestinal flora alteration of breastfeeding infant; advise a woman to monitor breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash)

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibits relaxation of DNA; inhibits DNA gyrase in susceptible organisms; promotes breakage of double-stranded DNA

Absorption

Bioavailability (PO): ~50-85%

Peak plasma time (PO): Immediate-release, 0.5-2 hr; extended-release, 1-2.5 hr

Distribution

Distributed widely throughout body; tissue concentrations often exceed serum concentrations, especially in kidneys, gallbladder, liver, lungs, gynecologic tissue, and prostatic tissue; cerebrospinal fluid (CSF) concentration is 10% in noninflamed meninges and 14-37% in inflamed meninges; crosses placenta; enters breast milk

Protein bound: 20-40%

Vd: 2.1-2.7 L/kg

Metabolism

Metabolized in liver

Enzyme inhibitor: CYP1A2

Elimination

Half-life: 2-5 hr (children); 3-5 hr (adults)

Excretion: Urine (30-50%), feces (15-43%)

IV Incompatibilities

Additive: Aminophylline, amoxicillin, amoxicillin-clavulanate, amphotericin, ampicillin-sulbactam, ceftazidime, cefuroxime, clindamycin, floxacillin, heparin, piperacillin, sodium bicarbonate, ticarcillin

Y-site: Aminophylline, ampicillin-sulbactam, azithromycin, cefepime, dexamethasone sodium phosphate, furosemide, heparin, hydrocortisone sodium succinate, magnesium sulfate(?), methylprednisolone sodium succinate, phenytoin, potassium phosphates, propofol, sodium bicarbonate(?), sodium phosphates, total parenteral nutrition formulations, warfarin

IV Compatibilities

Solution: Compatible with most IV fluids

Additive: Amikacin, aztreonam, dobutamine, dopamine, fluconazole, gentamicin, lidocaine, linezolid, metronidazole (ready-to-use form is compatible; hydrochloride form in vial is incompatible), midazolam, potassium chloride, tobramycin

Y-site: Amiodarone, calcium gluconate, clarithromycin, digoxin, diphenhydramine, dobutamine, dopamine, linezolid, lorazepam, midazolam, promethazine, quinupristin/dalfopristin, tacrolimus

IV Administration

Infuse 1-2 mg/mL (diluted in D5W or NS) into large vein over 60 minutes

When administering intermittently through Y-site, temporarily discontinue primary solution

Stability

Stable at concentration of 0.5-2 mg/mL in D5W or NS for 14 days at room temperature or refrigerated