(ciprofloxacin injection)

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13 NONCLINICAL TOXICOLOGY

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below:

  • Salmonella/Microsome Test (Negative)
  • E. coli DNA Repair Assay (Negative)
  • Mouse Lymphoma Cell Forward Mutation Assay (Positive)
  • Chinese Hamster V79 Cell HGPRT Test (Negative)
  • Syrian Hamster Embryo Cell Transformation Assay (Negative)
  • Saccharomyces cerevisiae Point Mutation Assay (Negative)
  • Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
  • Rat Hepatocyte DNA Repair Assay (Positive)

Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results:

  • Rat Hepatocyte DNA Repair Assay
  • Micronucleus Test (Mice)
  • Dominant Lethal Test (Mice)

Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 mg/ kg and 750 mg/kg to rats and mice, respectively (approximately 1.7- times and 2.5- times the highest recommended therapeutic dose based upon body surface area, respectively).

Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon body surface area), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 to 32 weeks in mice treated concomitantly with UVA and other quinolones.5

In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown.

Fertility studies performed in male and female rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.6-times the highest recommended therapeutic oral dose based upon body surface area) revealed no evidence of impairment. Male rats received oral ciprofloxacin for 10 weeks prior to mating and females were dosed for 3 weeks prior to mating through Gestation Day 7.

13.2 Animal Toxicology and/or Pharmacology

Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested [see Warnings and Precautions (5.13)].

Damage of weight-bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3- times and 3.5-times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology after a treatment- free period of 5 months. At 10 mg/kg (approximately 0.6-times the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study, removal of weight bearing from the joint reduced the lesions but did not totally prevent them.

Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg (approximately 0.07-times the highest recommended therapeutic dose based upon body surface area). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration (approximately 0.2-times the highest recommended therapeutic dose based upon body surface area).

In dogs, ciprofloxacin at 3 mg/kg and 10 mg/kg by rapid intravenous injection (15 sec.) produces pronounced hypotensive effects. These effects are considered to be related to histamine release, since they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid intravenous injection also produces hypotension but the effect in this species is inconsistent and less pronounced.

In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.

Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.

Medication Guide

MEDICATION GUIDE

This Medication Guide has been approved by the U.S. Food and Drug Administration.

MEDICATION GUIDE
CIPROFLOXACIN (sip-row-FLOX-a-sin) INJECTION, USP
(in 5% Dextrose Injection)
(ciprofloxacin)
for intravenous infusion
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 can happen at the same time and 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.
1. 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 swelling of the tendons including the back of the ankle (Achilles), shoulder, hand, thumb, 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 weightThe tendon problems may be permanent.

2. 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. Stop taking ciprofloxacin immediately and talk to 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
  • numbness
  • weaknessCiprofloxacin may need to be stopped to prevent permanent nerve damage.

3. Central Nervous System (CNS) effects. Mental health problems and seizures have been reported in people who take fluoroquinolone antibacterial medicines, including ciprofloxacin. Tell your healthcare provider if you have a history of seizures before you start taking ciprofloxacin. CNS side effects may happen as soon as after taking the first dose of ciprofloxacin. Stop taking ciprofloxacin immediately and 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 or agitated
  • tremors
  • feel anxious or nervous
  • confusion
  • depression
  • reduced awareness of surroundings
  • 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
  • memory problems
  • false or strange thoughts or beliefs (delusions)The CNS changes may be permanent.

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 a 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 white 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 Injection, USP 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 about all your medical conditions, including 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 known 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, or heart attack, especially a condition called “QT prolongation”.
  • have low blood potassium (hypokalemia) or low magnesium (hypomagnesemia).
  • have or have had seizures.
  • have kidney problems. You may need a lower dose of ciprofloxacin if your kidneys do not work well.
  • have diabetes or problems with low blood sugar (hypoglycemia).
  • have joint problems including rheumatoid arthritis (RA)
  • have trouble swallowing pills.
  • 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 your breast milk.
    • You should not breastfeed during treatment with ciprofloxacin and for 2 days after taking your last dose of ciprofloxacin. You may pump your breast milk and throw it away during treatment with ciprofloxacin and for 2 days after taking your last dose of ciprofloxacin.
    • If you are taking ciprofloxacin for inhalation anthrax, you and your healthcare provider should decide whether you can continue breastfeeding while taking ciprofloxacin.
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 (antiarrhythmics).
    • an oral anti-diabetes medicine.
    • phenytoin (Fosphenytoin Sodium®, Cerebyx®, Dilantin-125®, Dilantin®, Extended Phenytoin Sodium®, Prompt Phenytoin Sodium®, Phenytek®).
    • cyclosporine (Gengraf®, Neoral®, Sandimmune®, Sangcya®).
    • a blood thinner (such as warfarin, Coumadin®, Jantoven®).
    • methotrexate (Trexall®).
    • ropinirole (Requip®).
    • clozapine (Clozaril®, Fazaclo® ODT®).
    • a Non-Steroidal Anti-Inflammatory Drug (NSAID). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take ciprofloxacin or other fluoroquinolones may increase your risk of central nervous system effects and seizures.
    • sildenafil (Viagra®, Revatio®).
    • duloxetine.
    • products that contain caffeine.
    • probenecid (Probalan®, Col-probenecid®).
Ask your healthcare provider for a list of these medicines if you are not sure.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take ciprofloxacin?
Taking all of your ciprofloxacin doses will help lower the chance that the bacteria will become resistant to ciprofloxacin. If you become resistant to ciprofloxacin, ciprofloxacin and other antibacterial medicines may not work for you in the future.
  • If you take too much ciprofloxacin, call your healthcare provider or get medical help right away.

What should I avoid while taking ciprofloxacin?

  • Ciprofloxacin 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 affects you.
  • Avoid sunlamps, tanning beds, and try to limit your time in the sun. Ciprofloxacin can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get a severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while you take ciprofloxacin, 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?

Ciprofloxacin may cause serious side effects, including:
  • See “What is the most important information I should know about ciprofloxacin?”
  • Serious allergic reactions. Serious allergic reactions, including death, can happen in people taking fluoroquinolones, including ciprofloxacin, even after only 1 dose. Stop taking ciprofloxacin and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction:
    • hives
    • trouble breathing or swallowing
    • swelling of the lips, tongue, face
    • throat tightness, hoarseness
    • rapid heartbeat
    • faint
    • skin rash
    Skin rash may happen in people taking ciprofloxacin even after only 1 dose. Stop taking ciprofloxacin at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to ciprofloxacin.
  • Liver damage (hepatotoxicity). Hepatotoxicity can happen in people who take ciprofloxacin. Call your healthcare provider right away if you have unexplained symptoms such as:
    • nausea or vomiting
    • stomach pain
    • fever
    • weakness
    • abdominal pain or tenderness
    • itching
    • unusual tiredness
    • loss of appetite
    • light colored bowel movements
    • dark colored urine
    • yellowing of the skin and whites of your eyes
    Stop taking ciprofloxacin and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to ciprofloxacin (a liver problem).
  • Aortic aneurysm and dissection. Tell your healthcare provider if you have ever been told that you have an aortic aneurysm, a swelling of the large artery that carries blood from the heart to the body. Get emergency medical help right away if you have sudden chest, stomach, or back pain.
  • Intestine infection (Clostridioides difficile - associated diarrhea). Clostridioides difficile-associated diarrhea (CDAD) can happen with many antibacterial medicines, including ciprofloxacin. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. CDAD can happen 2 or more months after you have finished your antibacterial medicine.
  • Serious heart rhythm changes (QT prolongation and torsade de pointes). Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. Ciprofloxacin may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this event are higher in people:
    • who are elderly.
    • with a family history of prolonged QT interval.
    • with low blood potassium (hypokalemia) or low magnesium (hypomagnesemia).
    • who take certain medicines to control heart rhythm (antiarrhythmics).
  • Joint Problems. Increased chance of problems with joints and tissues around joints in children under 18 years old can happen. Tell your child's healthcare provider if your child has any joint problems during or after treatment with ciprofloxacin.
  • Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking ciprofloxacin?”
  • Changes in blood sugar. People who take ciprofloxacin and other fluoroquinolone medicines with oral anti-diabetes medicines or with insulin can get low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia). Follow your healthcare provider's instructions for how often to check your blood sugar. If you have diabetes and you get low blood sugar while taking ciprofloxacin, stop taking ciprofloxacin and call your healthcare provider right away. Your antibiotic medicine may need to be changed.
The most common side effects of ciprofloxacin include:
  • nausea
  • diarrhea
  • changes in liver function tests
  • vomiting
  • rash
Tell your healthcare provider about any side effect that bothers you, or that does not go away.
These are not all the possible side effects of ciprofloxacin. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Keep ciprofloxacin and all medicines out of the reach of children.
General Information about the safe and effective use of ciprofloxacin.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ciprofloxacin for a condition for which it is not prescribed. Do not give ciprofloxacin to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about ciprofloxacin. If you would like more information about ciprofloxacin, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ciprofloxacin that is written for healthcare professionals.
What are the ingredients in ciprofloxacin?
Ciprofloxacin Injection, USP (in 5% Dextrose Injection):
  • Active ingredient: ciprofloxacin
  • Inactive ingredients: dextrose monohydrate as a tonicity agent, hydrochloric acid for pH adjustment, lactic acid as a solubilizing agent.

Brands listed are the trademarks of their respective owners.
Hospira
Distributed by Hospira, Inc.,
Lake Forest, IL 60045 USA

Revised: August 2022

L54USCFX00

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