May 23 2022

INTERACTIONS OF CIPROFLOXACIN
Introduction     

Ciprofloxacin is rapidly absorbed from the gastrointestinal tract when administered orally. The presence of food does not affect the extent of absorption, but decreases its rate. The absorbed fraction is 75-85%. Once in the body, the active substance is metabolised at least in four metabolites, including desethyleneciprofloxacin, sulfociprofloxacin, oxociprofloxacin and N-formylciprofloxacin. The plasma elimination half-life of this substance is 3-5 hours in normal subjects.

Ciprofloxacin is an inhibitor of CYP1A2, so that, those substances substrates of this isozyme (that means, metabolised by CYP1A2) results in increased plasma concentrations of medicines such as tizanidine, theophylline and caffeine, and can be produced adverse effects by these drugs.

The oral bioavailability in fasted healthy volunteers is 50-85% of the administered dose, reaching peak concentration at 0.5-2.3 hours. Both the Cmax and AUC are dose dependent for doses ranging between 250 and 1000 mg. In elderly patients the values ​​are slightly higher than in young adults for a given dose.

Ciprofloxacin diffuses readily into the bile, lungs, kidneys, liver, prostate, tonsils, urinary bladder, uterus, seminal fluid, endometrium, fallopian tubes and ovaries, reaching a concentration substantially higher than in plasma. However, in the CSF concentration may be usually 6-10% of the plasma. The drug crosses the placental barrier and is distributed in the amniotic fluid. It is also eliminated on human milk.

ANTACIDS, SUCRALFATE AND CHELATORS     

The concurrent administration of ciprofloxacin with pharmaceuticals containing multivalent cations such as aluminum or magnesium antacids, polymeric phosphate, such as sevelamer, lanthanum carbonate, sucralfate, didanosine chewable tablets and other substances with calcium, iron or zinc may substantially decrease absorption of the quinolone.

The administration of antacids within 4 hours before taking ciprofloxacin significantly decreased absorption. Antacid administration six hours before or two hours after of the ciprofloxacin not affect the absorption of the latter.

In a study in healthy volunteers, coadministration of aluminum hydroxide or calcium carbonate reduced the bioavailability of ciprofloxacin to 15 and 60% respectively. Other data indicate reductions of up to 90%.

It has been reported the case of a patient with 63, whose response to treatment with ciprofloxacin was insufficient. The problem has been attributed to the concurrent administration of 1 g sucralfate three times daily, as well as taking aluminum hydroxide and magnesium. The interaction was discovered 13 days after initiation of treatment with ciprofloxacin.

The mechanism involves the chelation and subsequent decreased absorption of fluoroquinolone. Ciprofloxacin should be taken 2 hours before or six hours after taking these medications.

When taken together ciprofloxacin and calcium polycarbophil is produced a decrease of the absorption of the quinolone, caused by the formation of chelates. Avoid concurrent administration of these medications.

When administered with ciprofloxacin calcium carbonate is produced a reduction in Cmax and AUC of 43% of the quinolone with respect to the taking of the antibacterial alone (P <.05). It is recommended that patients receiving ciprofloxacin to abstain to take calcium supplements or, at least, take ciprofloxacin two hours before the calcium supplement.

Coadministration of ciprofloxacin with sucralfate produces a reduction in AUC, passing from 8.8 to 1.1 mcg.hr / mL (P <0.005). Similarly, the Cmax passes from 2 to 0.2 mcg / ml (P <0.005).

According to the data provided, it is preferable not to use these medications together. However, some studies in healthy volunteers indicate that it is advisable to administer ciprofloxacin between two and six hours before taking sucralfate, giving it time to absorb this, which would minimize the possible effect of this substance. In patients with slow gastric emptying, is more difficult to avoid interaction.

ALVIMOPAN     

The Alvimopan is a mu-receptor antagonist that blocks the effects of opioids in the gastrointestinal tract, respecting the analgesic effects. On concurrent administration of ciprofloxacin, the almivopan metabolites concentration is reduced by 99.2% (90% CI 98.8-99.5%). The interaction is established very quickly and recovery is slow. The Cmax of this drug is reduced by 24%, which has no clinical significance by itself.

This interaction may be important in patients with high concentrations of almivopan metabolites in the plasma prior to the administration of ciprofloxacin, but is not relevant if the taking of ciprofloxacin coincides with a modest level of metabolites of that substance.

ANTIARRHYTHMICS CLASS IA AND III     

When using both these drugs and ciprofloxacin should be monitored closely to patients, as they may have an additive effect on QT prolongation.

ORAL ANTICOAGULANTS     

Simultaneous administration enhances the effect of the anticoagulant . The risk may vary depending on the underlying infection, age and general condition of the patient. One study concludes that the extended-release tablets of the fluoroquinolone not appear to affect the pharmacokinetics of warfarin.

The INR should be checked frequently in these cases, adjusting the dose of anticoagulant as concurrent treatment with ciprofloxacin is associated with an elevated risk of bleeding (OR 2.74, 95% CI: 1.80-4.18).

NSAIDs     

It is known from preclinical studies that concurrent administration of anti-inflammatory drugs (but not acetyl salicylic acid) and ciprofloxacin or other quinolones at high doses can cause seizures. It is believed that NSAIDs may potentiate the CNS stimulating effects of quinolones.

Diclofenac used concurrently with ciprofloxacin increases the AUC, Cmax and Tmax and reduces total clearance of the latter. A usual dose seems to have no clinical relevance.

A woman of 68 years, chronically treated with NSAIDs and chloroquine, experienced dizziness, anxiety and tremor when initiates treatment with ciprofloxacin by osteitis. The patient improved dramatically by removing NSAIDs. By reintroducing indomethacin, developed signs and symptoms of peripheral neuropathy, which gave way in part to remove the ciprofloxacin.

The potentiation of adverse neurological effects of ciprofloxacin when taken together with anti-inflammatory or chloroquine may depend on reducing the effects of gamma-aminobutyric acid or perhaps a reduced clearance of ciprofloxacin.

AZATHIOPRINE/OLANZAPINE/VALSARTAN     

It has been published at least one case of marked QT prolongation in an elderly woman in prolonged treatment with azathioprine, olanzapine and valsartan after receiving ciprofloxacin IV.

AZIMILIDE     

It has been described the case of a man with an implanted defibrillator that coadministration of ciprofloxacin and azimilide produced QT prolongation and multiple episodes of torsades de pointes. Has not been determined the mechanism of this interaction, that should be considered when administering both drugs at once.

AZLOCILLIN     

The total clearance, volume of distribution and ciprofloxacin urinary fraction suffer a significant decrease when this drug is administered with azlocillin. This does not appear to affect the bioavailability of the latter. Toxic effects may occur when administered concurrently.

CAFFEINE     

Ciprofloxacin decreases caffeine clearance, extend its half life and inhibits the formation of paraxanthine. Concurrent administration with ciprofloxacin rises the level of caffeine . This interaction is due to inhibition of CYP1A2 by the former.

At therapeutic doses, the AUC and half-life values doubled compared to controls (77.8 versus 31.8mg/Lh and 9.7 versus 4.5 hours, respectively). This interaction is dose dependent.

The woman has more pronounced pharmacokinetic variations, being apparently greater the enzymatic inhibition and interaction than in men. However, an adjustment based on body weight reveals that there are no significant differences between the sexes.

CARBAMAZEPINE     

This anticonvulsant is an inducer of CYP1A2 and CYP3A4. The ciprofloxacin increased Cmax, AUC and t ½ while decreasing clearance and volume of distribution when administered simultaneously with the anticonvulsant. It is considered that the mechanism of interaction resides in the inhibition of CYP3A4 by the ciprofloxacin. It is necessary to adjust the dose of carbamazepine and monitor their levels when administered concurrently.

CYCLOSPORINE     

Some quinolone, including ciprofloxacin, have been related to an increased creatinine in patients taking both drugs. Furthermore,have been published observations that also describe increases in cyclosporine concentration .

Two case reports suggest that the combined use of these drugs can lead to acute kidney failure. Is recommended to monitor renal function simultaneously and the level of cyclosporine when administered simultaneously. However, in some studies no were no significant differences of the pharmacokinetic parameters of cyclosporine with or without concomitant intake of ciprofloxacin.

A 38 year old male with aplastic anemia of the red series was subjected to treatment with cyclosporine at 200 mg daily. At day 41, was increased immunosuppressive dose until 250 mg/day and 4 days later was admitted to the hospital for a febrile syndrome, being treated with ciprofloxacin IV, registering a cyclosporine level of 297 ng/mL, which forced return to the initial dose of cyclosporine. Following discontinuation of ciprofloxacin days later, cyclosporine concentration returns to normal level. These data are highly suggestive of drug interaction.

CHLOROQUINE     

Coadministration of chloroquine increased cumulative concentration of ciprofloxacin and its excretion. Also descends Cmax of ciprofloxacin.

CLOZAPINE     

Co-administration of both drugs increases levels of clozapine and its metabolite N-desmethylclozapine by 30%. There is a correlation between the concentration of clozapine and clozapine and N-desmethylclozapine increase(r = 0.90, P <0.01). Should be noted that even a small dose of ciprofloxacin may disproportionately increase the concentration of clozapine. The mechanism of interaction resides in the inhibition of CYP1A2 and CYP3A4.

It is advisable to carefully monitor the patient and rule out adverse effects of the antipsychotic drug, and making dose adjustment reducing it from the start, monitoring its blood level early and repeatedly. This interaction is dose-dependent: the higher the dose of ciprofloxacin greater influence on the level of clozapine, although ciprofloxacin, even at low doses, may increase moderately blood clozapine.

Some authors recommend using a different antibacterial or reduce dose and monitor levels of clozapine.

FOOD     

When ciprofloxacin tablets are administered concurrently with the meal is produced a delay in absorption resulting in a delay of one hour of peak concentration, unlike the suspension, which does not experience variations with respect the fasted state. Together, the extent of absorption is not affected in either case.

However, more frequent interactions, which can lead to failure of treatment are related to the products, not the meals.

DIAZEPAM     

Pretreatment with ciprofloxacin significantly reduced the clearance of diazepam, that goes down from 19.5 ml.h-1 kg-1 to 12.3 ml.h-1 kg-1 when taken at the same time. The t1/2 of diazepam goes up from 36.7 to 71.1 h if administered both simoultaneously. However, no significant changes were detected in psychometric tests or other indicators of psychomotor performance or level of consciousness.

DIDANOSINE     

As indicated above, the joint use with didanosine reduces ciprofloxacin absorption due to chelation with aluminum and magnesium-containing tablets of this substance.

A study in 12 healthy volunteers showed that while the maximum concentration of ciprofloxacin reached alone 3.38 + / - 0.63 mcg / mL, fell to 0.25 + / - 0.21 mcg / mL when administered with didanosine (p <0.0001). The mean AUC decreased from 15.50 + / - 2.69 mcg.hr / mL to 0.26 + / - 0.21 mcg.hr / mL (p <0.0001).

It is advisable to avoid taking together both substances.

DULOXETINE     

Clinical studies have shown that duloxetine administered with potent CYP1A2 inhibitors, as ciprofloxacin, suffers an elevation of its concentration, which can be increased by up to 5 times its initial parameters (AUC, Cmax). There are no published observations in this respect but theoretically can be expected to occur.

PHENYTOIN     

Have been published observations of increase and decrease of the plasma level of the anticonvulsant by the joint use of both drugs. However, in most cases decreases were observed in pharmacokinetic parameters of phenytoin 30-80%. Some patients may need a double dose of the initial to reach values ​​within the therapeutic range. When you remove the antibacterial, phenytoin should carefully adjusted to avoid poisoning by this substance.

FOSCARNET     

There are two reported cases of AIDS patients who had generalized tonic-clonic seizures while receiving foscarnet and ciprofloxacin. No patient had high risk previous of seizures. Co-administration of both drugs may predispose to seizures.

GLIBENCLAMIDE     

Concurrent use of glibenclamide has infrequently led to severe hypoglycemia with elevated levels of anti-diabetic drug. As is known, glibenclamide is metabolized by CYP450, which is inhibited in part by the ciprofloxacin. For some authors, the mechanism of the interaction is multifactorial.

Although the data available in the literature are controversial, this possibility should be considered in patients treated with this antidiabetic, when ciprofloxacin treatment is needed.

INDOMETHACIN     

It has published a case of filing a precipitate formed by indomethacin and ciprofloxacin on the eyes of a patient undergoing therapeutic keratectomy. In the case of topical ocular use should be avoided joint use of both drugs, particularly when there are large epithelial defects, that could favor deposition in stroma.

ISONIAZID     

Ciprofloxacin delays the start but not the extent of absorption of isoniazid. A study in healthy volunteers showed a delay of an hour to reach the tmax and a slight reduction in Cmax. This interaction has been linked to the inhibition of cholinergic neurotransmission caused by ciprofloxacin, that can inhibit gastric motility, delaying gastric emptying. This interaction is not clinically relevant.

IRON     

Ferrous sulfate can reduce the absorption of ciprofloxacin by chelation. As in the case of antacids, ciprofloxacin can be taken two hours before or six hours after the iron salt.

The plasma concentration and AUC of ciprofloxacin are substantially reduced when administered with 300 mg of ferrous sulfate (from 3.0 to 2.0 mg / L, P <0.05 and from 12.3 to 6.7 mg / L h, P <0.01 respectively). Some results suggest that Fe + + turns into Fe + + +, forming a complex of ferric ion-ciprofloxacin by interacting with the groups 3-carboxylic and 4-keto of ciprofloxacin, that probably is the cause of the reduction in its bioavailability in presence of iron.

SELECTIVE INHIBITORS SEROTONIN REUPTAKE     

A case report of serotonin syndrome has been attributed to pharmacokinetic and pharmacodynamic interaction between three SSRIs and ciprofloxacin. The author of the observation recommends caution in patients receiving this type of antidepressant, when it is necessary to add other serotonergic jointly with inhibitors of CYP450, as in the case of ciprofloxacin.

ITRACONAZOLE     

Ciprofloxacin significantly increased the Cmax and AUC of itraconazole by 53.13% and 82.46% respectively. Therefore, the combined use can lead to an increase in adverse effects. The antibacterial interacts inhibiting CYP3A4.

If used at the same time should be reduced dose of itraconazole and closely monitor the patient.

LIDOCAINE     

CYP1A2 plays an important role in the biotransformation of lidocaine.

A study in 9 healthy volunteers using lidocaine IV and ciprofloxacin together resulted in an increase in Cmax and AUC of the first of 12% and 26% respectively. This elevation was well tolerated, but it should be noted the possibility of interaction when combining the two drugs, as ciprofloxacin can increase the systemic toxicity of lidocaine.

METHADONE     

Methadone can cause an increased risk of elevated QT and torsades de pointes. These disorders can also be produced by ciprofloxacin, when there are other risk factors. It has been published one single case of QT prolongation and torsades de pointes in a patient on methadone after add ciprofloxacin.

It has been published a case of interaction in a patient treated with methadone for six years without incident, which suffered an episode of deep sedation, confusion and respiratory depression by adding ciprofloxacin. The authors consider likely that were due to inhibition of CYP1A2 and CYP3A4 isoenzymes.

Ciprofloxacin should be used with caution in patients receiving methadone.

METOCLOPRAMIDE     

Metoclopramide accelerates the absorption of oral ciprofloxacin, reducing the time it takes for the substance to reach its maximum plasma concentration. Clinically unimportant.

METHOTREXATE     

Ciprofloxacin inhibits renal tubular transport of methotrexate, leading to an increase in plasma levels, which increases the risk of toxic effects of this drug.

Patients undergoing methotrexate therapy should be monitored when it is necessary to add ciprofloxacin treatment. It is advisable to avoid using high-dose ciprofloxacin combination with methotrexate.

MEXILETINE     

Ciprofloxacin slows elimination of mexiletine. Be taken into account this interaction, as it may have clinical importance and may require dose adjustment of mexiletine.

OMEPRAZOLE     

Concurrent use of ciprofloxacin has resulted in healthy volunteer studies in a reduction of 16% in Cmax and AUC of ciprofloxacin average. Monitor efficacy of ciprofloxacin.

PAPAVERETUM     

This substance leads to a significant reduction in antibacterial pharmacokinetic parameters. It is advisable not to use papaveretum premedication with systemic ciprofloxacin surgical prophylaxis.

ACETAMINOPHEN/PARACETAMOL     

In a clinical trial in healthy volunteers, paracetamol increased antibacterial concentration by 16%, increasing slightly Cmax and AUC. In contrast, paracetamol experienced a slight delay in onset of action. No clinical significance.

PENTOXIFYLLINE     

This is another interaction due to inhibition of CYP1A2 by the ciprofloxacin, which can result in an increased concentration of pentoxifylline.

PROBENECID     

Probenecid interferes with renal tubular secretion of ciprofloxacin and leads to a significant increase in the levels of this substance. The addition of probenecid reduces the mean clearance of ciprofloxacin by 65% (95% CI 59-71, P <.01). It is believed that the interaction occurs by competitive inhibition of renal tubular secretion.

Control the possible adverse effects of ciprofloxacin.

QUINIDINE     

A 51 years old woman, black, was admitted in hospital for shortness of breath, abdominal pain and atrial fibrillation. The patient was treated with diltiazem and procainamide, to which was added ciprofloxacin for suspected diverticulitis. Five days later, it was substitued procainamide, giving in its place quinidine due to adverse effects of the first. On the 7th day, quinidine concentration was 6.3 mcg / mL (normal 2-5), with normal QT interval.

Quinidine is metabolized by CYP3A4, which is moderately inhibited by ciprofloxacin. This illustrates the need to take into account this interaction, controlling quinidine levels and to assess its potential toxicity.

QUINUPRISTIN-DALFOPRISTIN     

In vitro tests, ciprofloxacin alone is bactericidal, but reduces its antibacterial capacity when combined with quinupristin and dalfopristin. The clinical significance of this antagonism in vitro is unknown.

RIFAMPICIN     

The interaction causes an elevation of the half-life, decreasing the peak concentration of rifampicin, with no significant change in AUC and volume of distribution. No important clinical significance.

ROPINIROLE     

A study in 12 patients receiving both drugs produced an increase in Cmax and AUC of ropinirole by 60% and 84%% respectively. The interaction is caused by the inhibition of CYP1A2.

Patients receiving both drugs should be monitored, especially the possible adverse effects of ropinirole, adjusting the dose of this, early and properly, if necessary. There is not always a correlation between plasma concentration and the effects of this drug.

ROPIVACAINE     

Ciprofloxacin discretely decreases the clearance of this anesthetic by inhibiting CYP1A2, slowing the formation of 3-OH-ropivacaine. There are large interindividual variations with respect to the magnitude of the interaction, so that in some subjects the administration of both drugs can produce toxic effects. Monitor patients carefully.

SEVELAMER     

Sevelamer is a cationic polymer bound phosphate. The Cmax and AUC (0 - infinity) of ciprofloxacin decrease significantly when administered simultaneously. The relative oral bioavailability of ciprofloxacin decreases by 48%. If possible, avoid concomitant use of both drugs.

SILDENAFIL     

Administration of 50 mg of sildenafil at the same time that 500 mg ciprofloxacin in healthy subjects doubles average sildenafil values of Cmax and AUC. This interaction is caused by inhibition of CYP3A4 by the antibacterial.

The combined use of these drugs should be done with great caution, adjusting the dose of sildenafil.

SIMVASTATIN     

Has been reported an unusual interaction with ciprofloxacin consisting in the production of rhabdomyolysis when given this substance to patients at term treatment with simvastatin (mechanism unknown).

THYROTOXICOSIS     

It has been reported the case of a 24 year old woman admitted to the hospital with seizures, severe myopathy and acute renal failure after taking ciprofloxacin due to sinusitis. The analysis revealed a thyroiditis associated with thyrotoxicosis. Ciprofloxacin-associated seizures are limited to people with pre-existing risk factors. In the case of untreated thyrotoxicosis, it is preferable to use another different antibiotic.

Seizures associated with the use of ciprofloxacin occur more frequently in patients with risk factors that can lead to drug accumulation in the body, as high doses, advanced age, renal failure, drug interactions, electrolyte abnormalities, electroconvulsive therapy, or a history of seizures.

TIZANIDINE     

Concomitant use of tizanidine is contraindicated, as it may cause an increase in the pharmacokinetic parameters of 7-10 times its previous value (Cmax, AUC). Ciprofloxacin also potentiates the hypotensive and sedative effects of tizanidine. The interaction occurs through inhibition of CYP1A2.

THEOPHYLLINE     

Co-administration of ciprofloxacin and theophylline reduces theophylline clearance which results in an elevation of serum levels of bronchodilator, with increased risk of adverse effects caused by theophylline toxicity.

Have been published observations of fatal or severe reactions by concurrent administration of ciprofloxacin and theophylline, including cardiac arrest, status epilepticus, and respiratory failure. Although similar effects have been reported in patients taking theophylline alone, ciprofloxacin may enhance these reactions.

If it can not avoid the concurrent use of these drugs should be monitored theophylline level by adjusting the dose of this drug to keep within the therapeutic range.

A study in 77 251 elderly patients treated with theophylline recorded 180 cases of hospitalization for toxic effects of theophylline. It is estimated that jointly taking with ciprofloxacin increased at twice the risk of theophylline toxicity (OR 1.86, 95% CI :1.18-2 .93).

VITAMINS C AND E     

Experimental studies in vitro indicate potential antagonistic properties of vitamins C and E when co-administered with ciprofloxacin.

ZOLPIDEM     

Ciprofloxacin interacts with zolpidem raising Cmax, tmax and AUC due to increasing bioavailability of hypnotic 46%, according to studies in healthy volunteers. Probably, this is a clinically significant interaction.

FRUIT JUICE     

Although ciprofloxacin is marginally bioequivalent when administered with orange juice, not the same when taken along with juice with added calcium.

The absorption of ciprofloxacin may be reduced by concomitant intake of fruit juices with calcium carbonate and grapes. Changes in pharmacokinetic parameters can diminish the clinical efficacy of antibacterial and facilitate the emergence of resistant strains.

To avoid these problems, it is not advisable to take ciprofloxacin at the same time that fruit juices.

additional Information     

Ciprofloxacin during pregnancy

Ciprofloxacin during lactation

Ciprofloxacin : Patient information

Brands of Ciprofloxacin in major markets

Date of update of this page: November 10, 2008.

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