Ciprofloxacin

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

BOXED WARNING SECTION

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

INDICATIONS & USAGE SECTION

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

Ciprofloxacin Tablets should be administered orally as described in the appropriate Dosage Guidelines tables.

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

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

DRUG INTERACTIONS SECTION

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 9: 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 and in postmarketing. Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology ( 12.3 ) ] . Duloxetine Avoid Use If unavoidable, monitor for duloxetine toxicity Five-fold increase in duloxetine exposure Caffeine/Xanthine Use with caution Ciprofloxacin inhibits the formation of paraxanthine after caffeine Derivatives Reduced clearance resulting in elevated levels and prolongation of serum half-life administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary. 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.

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

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

DESCRIPTION SECTION

Ciprofloxacin (Ciprofloxacin hydrochloride) Tablets are synthetic antimicrobial agents for oral administration. Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the monohydrochloride monohydrate salt 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. Its empirical formula is C 17 H 18 FN 3 O 3 •HCl•H 2 O and its chemical structure is as follows: Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C 17 H 18 FN 3 O 3 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 250 mg, 500 mg and 750 mg (ciprofloxacin equivalent) strengths. Ciprofloxacin tablets are white to slightly yellowish. The inactive ingredients are Lactose Monohydrate, Magnesium Stearate, Sodium Starch Gylcolate, and Starch 1500 (Modified Corn Starch).

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

15 REFERENCES

REFERENCES SECTION

21 CFR 314.510 (Subpart H–Accelerated Approval of New Drugs for Life-Threatening Illnesses). Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. 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. 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. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard–9 th Edition . CLSI Document M7-A9 [2012]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087- 1898. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; 24 th Informational Supplement . CLSI Document M100 S24 [2014]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087- 1898. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline–2 nd Edition . CLSI Document M45-A2 [2010]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087- 1898. Clinical and Laboratory Standards Institute (CLSI), Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard–11th Edition . CLSI Document M2-A11[2012]. Clinical and Laboratory Standards Institute, 950 West Valley Rd., Suite 2500, Wayne, PA. 19087- 1898. 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. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166:1184-7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993; 167:1239-42. Anti-infective Drugs Advisory Committee Meeting, April 3, 2012 - The efficacy of Ciprofloxacin for treatment of Pneumonic Plague.

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

Ciprofloxacin Tablets USP (white to off-white capsule-shaped tablets) containing 500 mg of ciprofloxacin and engraved with Bottle of 6...............................................................................(NDC 70934-965-06) Bottle of 14.............................................................................(NDC 70934-965-14) Bottle of 20.............................................................................(NDC 70934-965-20) Bottle of 30.............................................................................(NDC 70934-965-30) Bottle of 60.............................................................................(NDC 70934-965-60) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Advise the patient to read the FDA- approved patient labeling (Medication Guide)

SPL MEDGUIDE SECTION

SPL MEDGUIDE SECTION

Medication Guide CIPROFLOXACIN TABLETS (Sip roe flox a sin) for oral use Read this Medication Guide before you start taking Ciprofloxacin and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about Ciprofloxacin? Ciprofloxacin, a fluoroquinolone antibacterial medicine, can cause serious side effects. Some of these serious side effects could result in death. If you get any of the following serious side effects while you take Ciprofloxacin, you should stop taking Ciprofloxacin immediately and get medical help right away. Tendon rupture or swelling of the tendon (tendinitis). Tendon problems can happen in people of all ages who take Ciprofloxacin. Tendons are tough cords of tissue that connect muscles to bones. Symptoms of tendon problems may include: pain swelling tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites. The risk of getting tendon problems while you take Ciprofloxacin is higher if you: are over 60 years of age are taking steroids (corticosteroids) have had a kidney, heart, or lung transplant Tendon problems can happen in people who do not have the above risk factors when they take Ciprofloxacin. Other reasons that can increase your risk of tendon problems can include: physical activity or exercise kidney failure tendon problems in the past, such as in people with rheumatoid arthritis (RA) Stop taking Ciprofloxacin immediately and get medical help right away at the first sign of tendon pain, swelling, or inflammation. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. Tendon rupture can happen while you are taking or after you have finished taking Ciprofloxacin. Tendon ruptures can happen within hours or days of taking Ciprofloxacin and have happened up to several months after people have finished taking their fluoroquinolone. Stop taking Ciprofloxacin immediately and get medical help right away if you get any of the following signs or symptoms of a tendon rupture: hear or feel a snap or pop in a tendon area bruising right after an injury in a tendon area unable to move the affected area or bear weight Changes in sensation and possible nerve damage (Peripheral Neuropathy) .Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including Ciprofloxacin. Talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: pain burning tingling numbmbness weakness Ciprofloxacin may need to be stopped to prevent permanent nerve damage. 3. Central Nervous System (CNS) effects. Seizures have been reported in people who take fluoroquinolone antibacterial medicines, including Ciprofloxacin. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking Ciprofloxacin will change your risk of having a seizure.CNS side effects may happen as soon as after taking the first dose of Ciprofloxacin. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: seizures hear voices, see things, or sense things that are not there (hallucinations) feel restless tremors feel anxious or nervous confusion depression trouble sleeping nightmares feel lightheaded or dizzy feel more suspicious (paranoia) suicidal thoughts or acts headaches that will not go away, with or without blurred vision 4. Worsening of myasthenia gravis (a problem that causes muscle weakness). Fluoroquinolones like Ciprofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Tell your healthcare provider if you have any history of myasthenia gravis before you start taking Ciprofloxacin. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems. What is Ciprofloxacin? Ciprofloxacin is a fluoroquinolone antibacterial medicine used in adults age 18 years and older to treat certain infections caused by certain germs called bacteria. These bacterial infections include: urinary tract infection chronic prostate infection lower respiratory tract infection sinus infection skin infection bone and joint infection nosocomial pneumonia intra-abdominal infection, complicated infectious diarrhea typhoid (enteric) fever cervical and urethral gonorrhea, uncomplicated people with a low while blood cell count and a fever inhalational anthrax plague Studies of Ciprofloxacin for use in the treatment of plague and anthrax were done in animals only, because plague and anthrax could not be studied in people. Ciprofloxacin should not be used in patients with acute exacerbation of chronic bronchitis, acute uncomplicated cystitis, and sinus infections, if there are other treatment options available. Ciprofloxacin should not be used as the first choice of antibacterial medicine to treat lower respiratory tract infections caused by a certain type of bacterial called Streptococcus pneumoniae . Ciprofloxacin is also used in children younger than 18 years of age to treat complicated urinary tract and kidney infections or who may have breathed in anthrax germs, have plague or have been exposed to plague germs. Children younger than 18 years of age have a higher chance of getting bone, joint, or tendon (musculoskeletal) problems such as pain or swelling while taking Ciprofloxacin. Ciprofloxacin should not be used as the first choice of antibacterial medicine in children under 18 years of age. Who should not take Ciprofloxacin? Do not take Ciprofloxacin if you: Have ever had a severe allergic reaction to an antibacterial medicine known as a fluoroquinolone, or are allergic to ciprofloxacin hydrochloride or any of the ingredients in Ciprofloxacin. See the end of this Medication Guide for a complete list of ingredients in Ciprofloxacin. Also take a medicine called tizanidine (Zanaflex®). Ask your healthcare provider if you are not sure. What should I tell my healthcare provider before taking Ciprofloxacin? Before you take Ciprofloxacin, tell your healthcare provider if you: have tendon problems; Ciprofloxacin should not be used in patients who have a history of tendon problems have a disease that causes muscle weakness (myasthenia gravis); Ciprofloxacin should not be used in patients who have a history of myasthenia gravis have liver problems have central nervous system problems (such as epilepsy) have nerve problems; Ciprofloxacin should not be used in patients who have a history of a nerve problem called peripheral neuropathy have or anyone in your family has an irregular heartbeat, especially a condition called “QT prolongation” have or have had seizures have kidney problems. You may need a lower dose of Ciprofloxacin if your kidneys do not work well. have joint problems including rheumatoid arthritis (RA) have trouble swallowing pills have any other medical conditions are pregnant or plan to become pregnant. It is not known if Ciprofloxacin will harm your unborn baby. are breastfeeding or plan to breastfeed. Ciprofloxacin passes into breast milk. You and your healthcare provider should decide whether you will take Ciprofloxacin or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Ciprofloxacin and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take: a steroid medicine an anti-psychotic medicine a tricyclic antidepressant a water pill (diuretic) theophylline (such as Theo-24 ®, Elixophyllin ®, Theochron ®, Uniphyl ®, Theolair ®) a medicine to control your heart rate or rhythm (a...

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC: 70934-965-20