Ciproflaxin Tablets

WARNING

Fluoroquinolones, including ciprofloxacin, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid ciprofloxacin in patients with known history of myasthenia gravis (see WARNINGS).

DESCRIPTION

CLINICAL PHARMACOLOGY

Absorption

2505007501000	1.22.44.35.4	4.811.620.230.8

Parameters	500 mg q12h, P.O.	400 mg q12h, I.V.	750 mg q12h, P.O.	400 mg q8h, I.V.
AUC (mcg•hr/mL) Cmax (mcg/mL)	13.7a 2.97	12.7a 4.56	31.6b 3.59	32.9c 4.07

Distribution

Metabolism

Excretion

Drug-drug Interactions

Special Populations

MICROBIOLOGY

Susceptibility Tests

≤ 12≥ 4	Susceptible (S)Intermediate (I) Resistant (R)

≤ 1	Susceptible (S)

≤ 0.060.12 – 0.5≥ 1	Susceptible (S)Intermediate (I) Resistant (R)

E. faecalis E. coli H. influenzaea P. aeruginosa S. aureus C. jejunib N. gonorrhoeaec	ATCC 29212ATCC 25922ATCC 49247ATCC 27853ATCC 29213ATCC 33560ATCC 49226	0.25 – 2 0.004 – 0.015 0.004 – 0.03 0.25 – 1 0.12 – 0.5 0.06 – 0.25 and 0.03 – 0.12 0.001 – 0.008

≥ 2116 – 20≤ 15	Susceptible (S)Intermediate (I) Resistant (R)

≥ 21	Susceptible (S)

≥ 4128 – 40≤ 27	Susceptible (S)Intermediate (I) Resistant (R)

E. coli H. influenzaea N. gonorrhoeaeb P. aeruginosa S. aureus	ATCC 25922ATCC 49247ATCC 49226ATCC 27853ATCC 25923	30 – 4034 – 4248 – 5825 – 3322 – 30

INDICATIONS AND USAGE

Adult Patients

Adult and Pediatric Patients

CONTRAINDICATIONS

WARNINGS

Tendinopathy and Tendon Rupture

Exacerbation of Myasthenia Gravis

Pregnant Women

Pediatrics

Cytochrome P450 (CYP450)

Central Nervous System Disorders

Theophylline

Hypersensitivity Reactions

fever, rash, or severe dermatologic reactions (e.g., 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.

Pseudomembranous Colitis

Peripheral neuropathy

Syphilis

PRECAUTIONS

General

Central Nervous System

Renal Impairment

Photosensitivity/Phototoxicity

Information for 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. 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.
that fluoroquinolones like ciprofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems.
that antibacterial drugs including ciprofloxacin tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., 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.
that ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, or sucralfate, didanosine chewable/buffered tablets or pediatric powder, other highly buffered drugs, or with other products containing calcium, iron or zinc should be avoided. Ciprofloxacin may be taken two hours before or six hours after taking these products. 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.
that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash or other allergic reaction.
that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should 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, they should 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, patients should contact their physician.
that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should discontinue treatment and contact their physicians.
that ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.
that ciprofloxacin increases the effects of tizanidine. Patients should not use ciprofloxacin if they are already taking tizanidine.
that ciprofloxacin may increase the effects of theophylline and caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.
that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to notify their physician before taking this drug if there is a history of this condition.
that ciprofloxacin has been associated with an increased rate of adverse events involving joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform their child’s physician if the child has a history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their child’s physician of any joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS, PRECAUTIONS, Pediatric Use andADVERSE REACTIONS.)
that 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, patients should contact their physician as soon as possible.

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Teratogenic Effects. Pregnancy Category C

Nursing Mothers

Pediatric Use

Inhalational Anthrax (Post-Exposure)

Complicated Urinary Tract Infection and Pyelonephritis

Cystic Fibrosis

Geriatric Use

ADVERSE REACTIONS

Adverse Reactions in Adult Patients

Adverse Reactions in Pediatric Patients

In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3%, rhinitis 3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.

In addition to the events reported in pediatric patients in clinical trials, it should be expected that events reported in adults during clinical trials or post-marketing experience may also occur in pediatric patients.

All Patients (within 6 weeks)	31/335 (9.3%)	21/349 (6%)
95% Confidence Interval*	(-0.8%, +7.2%)
Age Group
≥ 12 months < 24 months ≥ 2 years < 6 years ≥ 6 years < 12 years ≥ 12 years to 17 years	1/36 (2.8%)5/124 (4%)18/143 (12.6%)7/32 (21.9%)	0/413/118 (2.5%)12/153 (7.8%)6/37 (16.2 %)

All Patients (within 1 year)	46/335 (13.7%)	33/349 (9.5%)
95% Confidence Interval*	(-0.6%, + 9.1%)

Post-Marketing Adverse Event Reports

Adverse Laboratory Changes

OVERDOSAGE

DOSAGE AND ADMINISTRATION

ADULTS

Urinary Tract	Acute Uncomplicated Mild/Moderate Severe/Complicated	250 mg250 mg500 mg	q 12 hq 12 hq 12 h	3 Days 7 to 14 Days 7 to 14 Days
Chronic Bacterial Prostatitis	Mild/Moderate	500 mg	q 12 h	28 Days
Lower Respiratory Tract	Mild/Moderate Severe/Complicated	500 mg750 mg	q 12 hq 12 h	7 to 14 days 7 to 14 days
Acute Sinusitis	Mild/Moderate	500 mg	q 12 h	10 days
Skin and Skin Structure	Mild/Moderate Severe/Complicated	500 mg750 mg	q 12 hq 12 h	7 to 14 Days 7 to 14 Days
Bone and Joint	Mild/Moderate Severe/Complicated	500 mg750 mg	q 12 hq 12 h	≥ 4 to 6 weeks ≥ 4 to 6 weeks
Intra-Abdominal*	Complicated	500 mg	q 12 h	7 to 14 Days
Infectious Diarrhea	Mild/Moderate/Severe	500 mg	q 12 h	5 to 7 Days
Typhoid Fever	Mild/Moderate	500 mg	q 12 h	10 Days
Urethral and Cervical Gonococcal Infections	Uncomplicated	250 mg	single dose	single dose
Inhalational anthrax (post-exposure)**		500 mg	q 12 h	60 Days

250 mg Tablet q 12 h 500 mg Tablet q 12 h 750 mg Tablet q 12 h	200 mg I.V. q 12 h 400 mg I.V. q 12 h 400 mg I.V. q 8 h

> 5030 – 505 – 29Patients on hemodialysis orPeritoneal dialysis	See Usual Dosage. 250 – 500 mg q 12 h 250 – 500 mg q 18 h 250 – 500 mg q 24 h (after dialysis)

PEDIATRICS

Ciprofloxacin tablets should be administered orally as described in the Dosage Guidelines table. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed. (See ADVERSE REACTIONSand CLINICAL STUDIES.)

Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of complicated urinary tract infection and pyelonephritis. No information is available on dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency (i.e., creatinine clearance of < 50 mL/min/1.73m2).

PEDIATRIC DOSAGE GUIDELINES
Infection	Route of Administration	Dose(mg/kg)	Frequency	Total Duration
ComplicatedUrinary TractorPyelonephritis	Intravenous	6 to 10 mg/kg(maximum 400 mg perdose; not to be exceededeven in patients weighing > 51 kg)	Every 8hours	10-21 days*
(patients from 1 to 17 years of age)	Oral	10 mg/kg to 20 mg/kg (maximum 750 mg per dose; not to be exceededeven in patients weighing> 51 kg)	Every 12 hours
InhalationalAnthrax(Post-Exposure)**	Intravenous	10 mg/kg(maximum 400 mg perdose)	Every 12hours	60 days
Oral	15 mg/kg(maximum 500 mg per dose)	Every 12 hours

HOW SUPPLIED

ANIMAL PHARMACOLOGY

CLINICAL STUDIES

Complicated Urinary Tract Infection and Pyelonephritis – Efficacy in Pediatric Patients

	Ciprofloxacin	Comparator
Randomized Patients	337	352
Per Protocol Patients	211	231
Clinical Response at 5 to 9 Days Post-Treatment	95.7% (202/211)	92.6% (214/231)
	95% CI [-1.3%, 7.3%]
Bacteriologic Eradication by Patient at 5 to 9 Days Post-Treatment*	84.4% (178/211)	78.3% (181/231)
	95% CI [-1.3%, 13.1%]
Bacteriologic Eradication of the Baseline Pathogen at 5 to 9 Days Post-Treatment
Escherichia coli	156/178 (88%)	161/179 (90%)

INHALATIONAL ANTHRAX IN ADULTS AND PEDIATRICS – ADDITIONAL INFORMATION

REFERENCES

Revised: 03/2011

National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
Clinical and Laboratory Standards Institute, Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline., CLSI Document M45-A, Vol. 26, No. 19, CLSI, Wayne, PA, 2006.
National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests-Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
Report 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.
21 CFR 314.510 (Subpart H – Accelerated Approval of New Drugs for Life-Threatening Illnesses).
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.
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.

MEDICATION GUIDE

What is the most important information I should know about ciprofloxacin tablets?

See the section “What are the possible side effects of ciprofloxacin tablets?” for more information about side effects.

Tendon rupture or swelling of the tendon (tendinitis)Tendons are tough cords of tissue that connect muscles to bones. Pain, swelling, tears, and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites can happen in people of all ages who take fluoroquinolone antibiotics, including ciprofloxacin tablets. The risk of getting tendon problems is higher if you: are over 60 years of age are taking steroids (corticosteroids) have had a kidney, heart, or lung transplant.Swelling of the tendon (tendinitis) and tendon rupture (breakage) have also happened in patients who take fluoroquinolones who do not have the above risk factors. Other reasons for tendon ruptures can include: physical activity or exercise kidney failure tendon problems in the past, such as in people with rheumatoid arthritis (RA)
Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking ciprofloxacin tablets until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. 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. Talk to your healthcare provider about the risk of tendon rupture with continued use of ciprofloxacin tablets. You may need a different antibiotic that is not a fluoroquinolone to treat your infection.
Tendon rupture can happen while you are taking or after you have finished taking ciprofloxacin tablets. Tendon ruptures have happened up to several months after patients have finished taking their fluoroquinolone.
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
Worsening of myasthenia gravis (a disease which causes muscle weakness). Fluoroquinolones like ciprofloxacin tablets may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.

What are ciprofloxacin tablets?

Who should not take ciprofloxacin tablets?

have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are allergic to any of the ingredients in ciprofloxacin tablets. Ask your healthcare provider if you are not sure. See the list of ingredients in ciprofloxacin tablets at the end of this Medication Guide.
also take a medicine called tizanidine. Serious side effects from tizanidine are likely to happen.

What should I tell my healthcare provider before taking ciprofloxacin tablets?

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal and dietary supplements. Ciprofloxacin tablets and other medicines can affect each other causing side effects. The risk of getting tendon problems is higher if you:

Ask your healthcare provider if you are not sure if any of your medicines are listed above.Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

have tendon problems
have central nervous system problems (such as epilepsy)
have nerve problems
have or anyone in your family has an irregular heartbeat, especially a condition called “QT prolongation”
have a history of seizures
have kidney problems. You may need a lower dose of ciprofloxacin tablets if your kidneys do not work well.
have rheumatoid arthritis (RA) or other history of joint problems
have trouble swallowing pills
are pregnant or planning to become pregnant. It is not known if ciprofloxacin tablets will harm your unborn child.
are breast-feeding or planning to breast-feed. Ciprofloxacin passes into breast milk. You and your healthcare provider should decide whether you will take ciprofloxacin tablets or breastfeed.

How should I take ciprofloxacin tablets?

If you have been prescribed ciprofloxacin tablets after being exposed to anthrax:

Take ciprofloxacin tablets exactly as prescribed by your healthcare provider.
Take ciprofloxacin tablets in the morning and evening at about the same time each day. Swallow the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you can not swallow the tablet whole.
Ciprofloxacin tablets can be taken with or without food.
Ciprofloxacin tablets should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone, but may be taken with a meal that contains these products.
Drink plenty of fluids while taking ciprofloxacin tablets.
Do not skip any doses, or stop taking ciprofloxacin tablets even if you begin to feel better, until you finish your prescribed treatment, unless: you have tendon effects (see “What is the most important information I should know about ciprofloxacin tablets?”), you have a serious allergic reaction (see “What are the possible side effects of ciprofloxacin tablets?”), or your healthcare provider tells you to stop.

What should I avoid while taking ciprofloxacin tablets?

Ciprofloxacin tablets can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how ciprofloxacin tablets affects you.
Avoid sunlamps, tanning beds, and try to limit your time in the sun. Ciprofloxacin tablets can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking ciprofloxacin tablets, call your healthcare provider right away. You should use a sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight.

What are the possible side effects of ciprofloxacin tablets?

Seizures have been reported in people who take fluoroquinolone antibiotics including ciprofloxacin tablets. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking ciprofloxacin tablets will change your risk of having a seizure.Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of ciprofloxacin tablets. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:

Allergic reactions can happen in people taking fluoroquinolones, including ciprofloxacin tablets, even after only one dose. Stop taking ciprofloxacin tablets and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction:

Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including ciprofloxacin tablets. 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:

See “What should I avoid while taking ciprofloxacin tablets?”

Increased chance of problems with joints and tissues around joints in children under 18 years old. Tell your child’s healthcare provider if your child has any joint problems during or after treatment with ciprofloxacin tablets.The most common side effects of ciprofloxacin tablets include:

These are not all the possible side effects of ciprofloxacin tablets. Tell your healthcare provider about any side effect that bothers you, or that does not go away.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Ciprofloxacin tablets can cause side effects that may be serious or even cause death. See “What is the most important information I should know about ciprofloxacin tablets?”