WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS
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displayName: BOXED WARNING SECTION
FDA Article Code: 34066-1
• Fluoroquinolones, including ciprofloxacin, have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together [see Warnings and Precautions (5.1)] including:
• Tendinitis and tendon rupture [see Warnings and Precautions (5.2)]
• Peripheral neuropathy [see Warnings and Precautions (5.3)]
• Central nervous system effects [see Warnings and Precautions (5.4)]
Discontinue ciprofloxacin immediately and avoid the use of fluoroquinolones, including ciprofloxacin, in patients who experience any of these serious adverse reactions [see Warnings and Precautions (5.1)]
. Fluoroquinolones, including ciprofloxacin, may exacerbate muscle weakness in patients with myasthenia gravis. Avoid ciprofloxacin in patients with known history of myasthenia gravis [see Warnings and Precautions (5.5)].
• Because fluoroquinolones, including ciprofloxacin, have been associated with serious adverse reactions [see Warnings and Precautions (
5.1–5.15
)], reserve ciprofloxacin for use in patients who have no alternative treatment options for the following indications:
• Acute exacerbation of chronic bronchitis [see Indications and Usage (1.10)]
• Acute uncomplicated cystitis [see Indications and Usage (1.11)]
• Acute sinusitis [see Indications and Usage (1.12)]
1 INDICATIONS AND USAGE
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displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9
Ciprofloxacin tablets are indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions and patient populations listed below.
2 DOSAGE AND ADMINISTRATION
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displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7
Ciprofloxacin tablets should be administered orally as described in the appropriate Dosage Guidelines tables.
6 ADVERSE REACTIONS
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displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4
The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
• Disabling and Potentially Irreversible Serious Adverse Reactions [see Warnings and Precautions (5.1)]
• Tendinitis and Tendon Rupture [see Warnings and Precautions (5.2)]
• Peripheral Neuropathy [see Warnings and Precautions (5.3)]
• Central Nervous System Effects [see Warnings and Precautions (5.4)]
• Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.5)]
• Other Serious and Sometimes Fatal Adverse Reactions [see Warnings and Precautions (5.6)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
• Hepatotoxicity [see Warnings and Precautions (5.8)]
• Serious Adverse Reactions with Concomitant Theophylline [see Warnings and Precautions (5.9)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.10)]
• Prolongation of the QT Interval [see Warnings and Precautions (5.11)]
• Musculoskeletal Disorders in Pediatric Patients [see Warnings and Precautions (5.12)]
• Photosensitivity/Phototoxicity [see Warnings and Precautions (5.13)]
• Development of Drug Resistant Bacteria [see Warnings and Precautions (5.14)]
7 DRUG INTERACTIONS
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displayName: DRUG INTERACTIONS SECTION
FDA Article Code: 34073-7
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 11: 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 (4.2)
].
|
| 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 (5.9)
.]
|
| 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 (5.11)
and
Use in
Specific Populations (8.5)
].
|
| 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 (6.1)
.]
|
| 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 (5.16)
].
|
| 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 in and postmarketing.
|
| Sildenafil
|
Use with caution Two-fold increase in exposure
|
Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3
)].
|
| 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 (2.4)]
.
|
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.
|
10 OVERDOSAGE
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displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Empty the stomach by inducing vomiting or by gastric lavage. Observe the patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria and administration of magnesium, aluminum, or calcium containing antacids which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (less than 10%) is removed from the body after hemodialysis or peritoneal dialysis.
11 DESCRIPTION
id: ef67109b-3772-4731-86a2-803e01192a8c
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3
Ciprofloxacin tablets USP are synthetic antimicrobial agents for oral administration.Ciprofloxacin hydrochloride USP, a fluoroquinolone, is the monohydrochloride monohydratesalt of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid.It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8. Itsmolecular formula is C17H18FN3O3•HCl•H2O and its chemical structure is as follows:17H18FN3O3•HCl•H2O and its chemical structure is as follows:
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecar boxylic acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4. It is a faintly yellowish to light yellow crystalline substance and its chemical structure is as follows:
Ciprofloxacin film-coated tablets are available in 100 mg, 250 mg, 500 mg and 750 strengths.Ciprofloxacin tablets are white. The inactive ingredients are colloidal silicon dioxide,hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, sodiumstarch glycolate, corn starch and titanium dioxide.
15 REFERENCES
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displayName: REFERENCES SECTION
FDA Article Code: 34093-5
1. 21 CFR 314.510 (Subpart H–Accelerated Approval of New Drugs for Life-Threatening Illnesses).
2. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195.
3. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6):1336-1339.
4. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69:83-89.
5. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard–Tenth Edition. CLSI Document M7-A10 [2015]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087-1898.
6. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-seventh Informational Supplement. CLSI Document M100 S27 [2017]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087-1898.
7. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline–Third Edition. CLSI Document M45-A3 [2016]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087-1898.
8. Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard–Twelfth Edition. CLSI Document M2-A12[2015]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087-1898.
9. CReport presented at the FDA’s Anti-Infective Drug and Dermatological Drug Product’s Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA.
10. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7.
11. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993; 167:1239-42.
12. Anti-infective Drugs Advisory Committee Meeting, April 3, 2012 – The efficacy of ciprofloxacin for treatment of Pneumonic Plague.
16 HOW SUPPLIED/STORAGE AND HANDLING
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displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5
Product: 63629-1724
NDC: 63629-1724-6 10 TABLET, FILM COATED in a BOTTLE
NDC: 63629-1724-4 60 TABLET, FILM COATED in a BOTTLE
NDC: 63629-1724-7 28 TABLET, FILM COATED in a BOTTLE
NDC: 63629-1724-8 2 TABLET, FILM COATED in a BOTTLE
NDC: 63629-1724-0 7 TABLET, FILM COATED in a BOTTLE
NDC: 63629-1724-1 14 TABLET, FILM COATED in a BOTTLE
NDC: 63629-1724-2 30 TABLET, FILM COATED in a BOTTLE
NDC: 63629-1724-9 40 TABLET, FILM COATED in a BOTTLE
NDC: 63629-1724-3 20 TABLET, FILM COATED in a BOTTLE
NDC: 63629-1724-5 6 TABLET, FILM COATED in a BOTTLE
17 PATIENT COUNSELING INFORMATION
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displayName: INFORMATION FOR PATIENTS SECTION
FDA Article Code: 34076-0
Advise the patient to read the FDA-approved patient labeling (Medication Guide)
Serious Adverse Reactions
Advise patients to stop taking ciprofloxacin if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.
Inform patients of the following serious adverse reactions that have been associated with ciprofloxacin or other fluoroquinolone use:
• Disabling and potentially irreversible serious adverse reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of ciprofloxacin and may occur together in the same patient. Inform patients to stop taking ciprofloxacin immediately if they experience an adverse reaction and to call their healthcare provider.
· Tendinitis and tendon rupture: Instruct patients to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue ciprofloxacin treatment. Symptoms may be irreversible. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
· Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with ciprofloxacin use, symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, immediately discontinue ciprofloxacin and tell them to contact their physician.
· Central nervous system effects (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure): Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including Ciprofloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to CIPRO before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
· Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
· Hypersensitivity Reactions: Inform patients that ciprofloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
· Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking ciprofloxacin. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
· Dia
rrhea: Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, instruct patients to contact their physician as soon as possible.
· Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
· Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child’s physician if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric patients to notify their child’s physician of any joint-related problems that occur during or following ciprofloxacin therapy [see Warnings and Precautions (5.12) and Use in Specific Populations (8.4)].
· Tizanidine: Instruct patients not to use ciprofloxacin if they are already taking tizanidine. Ciprofloxacin increases the effects of tizanidine (Zanaflex®).
· Theophylline: Inform patients that ciprofloxacin may increase the effects of theophylline. Life-threatening CNS effects and arrhythmias can occur. Advise the patients to immediately seek medical help if they experience seizures, palpitations, or difficulty breathing.
· Caffeine: Inform patients that ciprofloxacin may increase the effects of caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones. Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, instruct them to wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, instruct patients to contact their physician.
Antibacterial Resistance
Inform patients that antibacterial drugs including ciprofloxacin tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When ciprofloxacin tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ciprofloxacin tablets or other antibacterial drugs in the future.
Administration Instructions
Administration with Food, Fluids, and Concomitant Medications
Inform patients that ciprofloxacin may be taken with or without food.
Inform patients to drink fluids liberally while taking ciprofloxacin to avoid formation of highly concentrated urine and crystal formation in the urine.
Inform patients that antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine should be taken at least two hours before or six hours after ciprofloxacin administration. Ciprofloxacin should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken with a meal that contains these products.
Drug Interactions Oral Antidiabetic Agents
Inform patients that hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents were co-administered; if low blood sugar occurs with ciprofloxacin, instruct them to consult their physician and that their antibacterial medicine may need to be changed.
Anthrax and Plague Studies
Inform patients given ciprofloxacin for these conditions that efficacy studies could not be conducted in humans for feasibility reasons. Therefore, approval for these conditions was based on efficacy studies conducted in animals.
Ciprofloxacin 500mg Tablet
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displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
