CIPROFLOXACIN Drug Interactions: What You Need to Know

INTERACTIONS 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.

Table

8: Drugs That are Affected by and Affecting Ciprofloxacin Drugs That are Affected by Ciprofloxacin Drug(s)

Recommendation Comments Tizanidine Contraindicated

Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications ( Error! Hyperlink reference not valid. )].

Theophylline Avoid

Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions ( Error! Hyperlink reference not valid. )].

Drugs

Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( Error! Hyperlink reference not valid. ) and Use in Specific Populations ( Error! Hyperlink reference not valid. )]. Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions ( Error! Hyperlink reference not valid. )].

Phenytoin

Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.

Cyclosporine

Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine. Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co- administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).

Methotrexate

Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.

Ropinirole

Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions ( Error! Hyperlink reference not valid. )].

Clozapine

Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. NSAIDs Use with caution 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 and in postmarketing.

Sildenafil

Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology ( Error! Hyperlink reference not valid. )].

Duloxetine Avoid Use

Five-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity.

Caffeine/Xanthine

Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.

Zolpidem Avoid

Use Co-administration with ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended. Drug(s)

Affecting

Pharmacokinetics of Ciprofloxacin Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( Error! Hyperlink reference not valid. )]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.

Interacting Drug Interaction Theophylline

Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( Error! Hyperlink reference not valid. )

Warfarin

Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding(7) Antidiabetic agents Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)

Phenytoin

Monitor phenytoin level (7)

Methotrexate

Monitor for methotrexate toxicity (7)

Cyclosporine

May increase serum creatinine. Monitor serum creatinine (7) Multivalent cation-containing products including antacids, metal cations or didanosine Decreased ciprofloxacin absorption. Take ciprofloxacin tablets 2 hours before or 6 hours after administration of multivalent cation containing drugs (7)

Click here to enter Contraindications

• Known hypersensitivity to ciprofloxacin or other quinolones ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. Error! Hyperlink reference not valid. )
• Concomitant administration with tizanidine Error! Hyperlink reference not valid.

4.1 Hypersensitivity Ciprofloxacin tablets are contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antibacterials, or any of the product components <span class="opacity-50 text-xs">[see Warnings and Precautions ( Error! Hyperlink reference not valid. )]</span>.

4.2 Tizanidine Concomitant administration with tizanidine is contraindicated <span class="opacity-50 text-xs">[see Drug Interactions ( Error! Hyperlink reference not valid. )]</span>.

AND PRECAUTIONS Click here to enter Warnings and Precautions

• Hypersensitivity and other serious reactions: Serious and sometimes fatal reactions (for example, anaphylactic reactions) may occur after the first or subsequent doses of ciprofloxacin. Discontinue ciprofloxacin at the first sign of skin rash, jaundice or any sign of hypersensitivity. ( Error! Hyperlink reference not valid. , 5.6 , Error! Hyperlink reference not valid. )
• Hepatotoxicity: Discontinue immediately if signs and symptoms of hepatitis occur. ( Error! Hyperlink reference not valid. )
• Clostridioides difficile-associated diarrhea: Evaluate if colitis occurs. ( Error! Hyperlink reference not valid. )
• QT Prolongation: Prolongation of the QT interval and isolated cases of torsade de pointes have been reported. Avoid use in patients with known prolongation, those with hypokalemia, and with other drugs that prolong the QT interval. ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )

5.1 Disabling and Potentially Irreversible Serious Adverse Reactions Including Tendinitis and Tendon Rupture, Peripheral Neuropathy, and Central Nervous System Effects Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. 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 ciprofloxacin. Patients of any age or without pre-existing risk factors have experienced these adverse reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )]</span>. Discontinue ciprofloxacin immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including ciprofloxacin, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

5.2 Tendinitis and Tendon Rupture Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of tendinitis and tendon rupture in all ages <span class="opacity-50 text-xs">[see Warnings and Precautions ( Error! Hyperlink reference not valid. ) and Adverse Reactions ( Error! Hyperlink reference not valid. )]</span> . This adverse reaction most frequently involves the Achilles tendon, and has also been reported with the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis or tendon rupture can occur, within hours or days of starting ciprofloxacin, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors 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. Discontinue ciprofloxacin immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including ciprofloxacin, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture <span class="opacity-50 text-xs">[see Adverse Reactions ( Error! Hyperlink reference not valid. )]</span>.

5.3 Peripheral Neuropathy Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of peripheral neuropathy. 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 fluoroquinolones, including ciprofloxacin. Symptoms may occur soon after initiation of ciprofloxacin and may be irreversible in some patients <span class="opacity-50 text-xs">[see Warnings and Precautions ( Error! Hyperlink reference not valid. ) and Adverse Reactions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )]</span>. Discontinue ciprofloxacin immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation, and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including ciprofloxacin, in patients who have previously experienced peripheral neuropathy <span class="opacity-50 text-xs">[see Adverse Reactions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )]</span>.

5.4 Central Nervous System Effects Psychiatric Adverse Reactions Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of psychiatric adverse reactions, including: toxic psychosis, psychotic reactions progressing to suicidal ideations/thoughts, hallucinations, or paranoia; depression, or self-injurious behavior such as attempted or completed suicide; anxiety, agitation, or nervousness; confusion, delirium, disorientation, or disturbances in attention; insomnia or nightmares; memory impairment. These reactions may occur following the first dose. Advise patients receiving ciprofloxacin to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care.

Central Nervous System Adverse Reactions

Fluoroquinolones, including ciprofloxacin, have been associated with an increased risk of seizures (convulsions), increased intracranial pressure (pscudotumor cerebri), dizziness, and tremors. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. Cases of status epilepticus have been reported. As with all fluoroquinolones, use ciprofloxacin with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (for example, certain drug therapy, renal dysfunction). If seizures occur, discontinue ciprofloxacin and institute appropriate care [see Adverse Reactions ( Error! Hyperlink reference not valid. ) and Drug Interactions ( Error! Hyperlink reference not valid. )].

5.5 Exacerbation of Myasthenia Gravis Fluoroquinolones, including ciprofloxacin, have neuromuscular blocking activity and 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 ciprofloxacin in patients with known history of myasthenia gravis <span class="opacity-50 text-xs">[see Adverse Reactions ( Error! Hyperlink reference not valid. )]</span>.

5.6 Other Serious and Sometimes Fatal Adverse Reactions Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported 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 (for example, 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. Discontinue ciprofloxacin immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted [see Adverse Reactions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )].

5.7 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving fluoroquinolone therapy, including ciprofloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, including intubation, as indicated <span class="opacity-50 text-xs">[see Adverse Reactions ( Error! Hyperlink reference not valid. )]</span>.

5.8 Hepatotoxicity Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, have been reported with ciprofloxacin. Acute liver injury is rapid in onset (range 1–39 days), and is often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic, or mixed. Most patients with fatal outcomes were older than 55 years old. In the event of any signs and symptoms of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), discontinue treatment immediately. There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin <span class="opacity-50 text-xs">[see Adverse Reactions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )]</span>.

5.9 Risk of Aortic Aneurysm and Dissection Epidemiologic studies report an increased rate of aortic aneurysm and dissection within two months following use of fluoroquinolones, particularly in elderly patients. The cause for the increased risk has not been identified. In patients with a known aortic aneurysm or patients who are at greater risk for aortic aneurysms, reserve ciprofloxacin for use only when there are no alternative antibacterial treatments available.

5.10 Serious Adverse Reactions with Concomitant Theophylline Serious and fatal reactions have been reported in patients receiving concurrent administration of ciprofloxacin and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Instances of nausea, vomiting, tremor, irritability, or palpitation have also occurred. Although similar serious adverse reactions have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate <span class="opacity-50 text-xs">[see Drug Interactions ( Error! Hyperlink reference not valid. )]</span>.

5.11 Clostridioides difficile -Associated Diarrhea Clostridioides difficile (C. difficile)- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ciprofloxacin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and institute surgical evaluation as clinically indicated <span class="opacity-50 text-xs">[see Adverse Reactions ( Error! Hyperlink reference not valid. )]</span>.

5.12 Prolongation of the QT Interval Some fluoroquinolones, including ciprofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and cases of arrhythmia. Cases of torsade de pointes have been reported during postmarketing surveillance in patients receiving fluoroquinolones, including ciprofloxacin. Avoid ciprofloxacin in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsade de pointes (for example, congenital long QT syndrome, uncorrected electrolyte imbalance, such as hypokalemia or hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class III antiarrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics. Elderly patients may also be more susceptible to drug-associated effects on the QT interval <span class="opacity-50 text-xs">[see Adverse Reactions ( Error! Hyperlink reference not valid. ), Use in Specific Populations ( Error! Hyperlink reference not valid. )]</span>.

5.13 Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals Ciprofloxacin is indicated in pediatric patients (less than 18 years of age) only for cUTI, prevention of inhalational anthrax (post exposure), and plague <span class="opacity-50 text-xs">[see Indications and Usage ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )]</span>. An increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues, has been observed <span class="opacity-50 text-xs">[see Adverse Reactions ( Error! Hyperlink reference not valid. )]</span>. 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( Error! Hyperlink reference not valid. ) and Nonclinical Toxicology ( Error! Hyperlink reference not valid. )]</span> .

5.14 Photosensitivity/Phototoxicity Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, 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 including ciprofloxacin after sun or UV light exposure. Therefore, avoid excessive exposure to these sources of light. Discontinue ciprofloxacin if phototoxicity occurs <span class="opacity-50 text-xs">[see Adverse Reactions ( Error! Hyperlink reference not valid. )]</span>.

5.15 Development of Drug Resistant Bacteria 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.

5.16 Potential Risks with Concomitant Use of Drugs Metabolized by Cytochrome P450 1A2 Enzymes Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Co-administration of 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 the co-administered drug and could lead to clinically significant pharmacodynamic adverse reactions of the co-administered drug <span class="opacity-50 text-xs">[see Drug Interactions ( Error! Hyperlink reference not valid. ) and Clinical Pharmacology ( Error! Hyperlink reference not valid. )]</span>.

5.17 Interference with Timely Diagnosis of 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. Perform a serologic test for syphilis in all patients with gonorrhea at the time of diagnosis. Perform follow-up serologic test for syphilis three months after ciprofloxacin treatment.

5.18 Crystalluria 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 <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( Error! Hyperlink reference not valid. )]</span>. Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Avoid alkalinity of the urine in patients receiving ciprofloxacin. Hydrate patients well to prevent the formation of highly concentrated urine <span class="opacity-50 text-xs">[see Dosage and Administration ( Error! Hyperlink reference not valid. )]</span>.

5.19 Blood Glucose Disturbances Fluoroquinolones, including ciprofloxacin, have been associated with disturbances of blood glucose, including symptomatic hyperglycemia and hypoglycemia, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic agent (for example, glyburide) or with insulin. In these patients, careful monitoring of blood glucose is recommended. Severe cases of hypoglycemia resulting in coma or death have been reported. If a hypoglycemic reaction occurs in a patient being treated with ciprofloxacin, discontinue ciprofloxacin and initiate appropriate therapy immediately <span class="opacity-50 text-xs">[see Adverse Reactions ( Error! Hyperlink reference not valid. ), Drug Interactions ( Error! Hyperlink reference not valid. )]</span> .