Chenodiol

Chenodiol Tablets, 250 mg

SPECIAL NOTE

Because of the potential hepatoxicity of Chenodiol, poor response rate in some subgroups of Chenodiol treated patients, and an increased rate of a need for cholecystectomy in other Chenodiol treated subgroups, Chenodiol is not an appropriate treatment for many patients with gallstones. Chenodiol should be reserved for carefully selected patients and treatment must be accompanied by systematic monitoring for liver function alterations. Aspects of patient selection, response rates and risks versus benefits are given in the insert.

DESCRIPTION

Chenodiol is the non-proprietary name for chenodeoxycholic acid, a naturally occurring human bile acid. It is a bitter-tasting white powder consisting of crystalline and amorphous particles freely soluble in methanol, acetone and acetic acid and practically insoluble in water. Its chemical name is 3α, 7α-dihydroxy-5β-cholan-24-oic acid (C24H40O4), it has a molecular weight of 392.58, and its structure is shown below;

Chenodeoxycholic Acid

Chenodiol film-coated tablets for oral administration contain 250 mg of Chenodiol.

Inactive ingredients: pregelatinized starch; silicon dioxide; microcrystalline cellulose, sodium starch glycollate; and magnesium stearate; the thin-film coating contains: opadry YS-2-7035 [consisting of methylcellulose and glycerin] and sodium lauryl sulfate

CLINICAL PHARMACOLOGY

At therapeutic doses, Chenodiol suppresses hepatic synthesis of both cholesterol and cholic acid, gradually replacing the latter and its metabolite, deoxycholic acid in an expanded bile acid pool. These actions contribute to biliary cholesterol desaturation and gradual dissolution of radiolucent cholesterol gallstones in the presence of a gall-bladder visualized by oral cholecystography. Chenodiol has no effect on radiopaque (calcified) gallstones or on radiolucent bile pigment stones.

Chenodiol is well absorbed from the small intestine and taken up by the liver where it is converted to its taurine and glycine conjugates and secreted in bile. Owing to 60 % to 80% first-pass hepatic clearance, the body pool of Chenodiol resides mainly in the enterohepatic circulation; serum and urinary bile acid levels are not significantly affected during Chenodiol therapy.

At steady-state, an amount of Chenodiol near the daily dose escapes to the colon and is converted by bacterial action to lithocholic acid. About 80% of the lithocholate is excreted in the feces; the remainder is absorbed and converted in the liver to its poorly absorbed sulfolithocholyl conjugates. During Chenodiol therapy there is only a minor increase in biliary lithocholate, while fecal bile acids are increased three- to fourfold.

Chenodiol is unequivocally hepatotoxic in many animal species, including sub-human primates at doses close to the human dose. Although the theoretical cause is the metabolite, lithocholic acid, an established hepatotoxin, and man has an efficient mechanism for sulfating and eliminating this substance, there is some evidence that the demonstrated hepatotoxicity is partly due to Chenodiol per se. The hepatotoxicity of lithocholic acid is characterized biochemically and morphologically as cholestatic.

Man has the capacity to form sulfate conjugates of lithocholic acid. Variation in this capacity among individuals has not been well established and a recent published report suggests that patients who develop Chenodiol-induced serum aminotransferase elevations are poor sulfators of lithocholic acid (seeADVERSE REACTIONS and WARNINGS).

General Clinical Results: Both the desaturation of bile and the clinical dissolution of cholesterol gallstones are dose-related. In the National Cooperative Gallstone Study (NCGS) involving 305 patients in each treatment group, placebo and Chenodiol dosages of 375 mg and 750 mg per day were associated with complete stone dissolution in 0.8%, 5.2% and 13.5%, respectively, of enrolled subjects over 24 months of treatment. Uncontrolled clinical trials using higher doses than those used in the NCGS have shown complete dissolution rates of 28 to 38% of enrolled patients receiving body weight doses of from 13 to 16 mg/kg/day for up to 24 months. In a prospective trial using 15 mg/kg/day, 31% enrolled surgical-risk patients treated more than six months (n = 86) achieved complete confirmed dissolutions.

Observed stone dissolution rates achieved with Chenodiol treatment are higher in subgroups having certain pretreatment characteristics. In the NCGS, patients with small {less than 15 mm in diameter} radiolucent stones, the observed rate of complete dissolution was approximately 20% on 750 mg/day. In the uncontrolled trails using 13 to 16 mg/kg/day doses of Chenodiol, the rates of complete dissolution for small radiolucent stones ranged from 42% to 60%. Even higher dissolution rates have been observed in patients with small floatable stones. (See Floatable versus Nonfloatable Stones, below). Some obese patients and occasional normal weight patients fail to achieve bile desaturation even with doses of Chenodiol up to 19 mg/kg/day for unknown reasons. Although dissolution is generally higher with increased dosage of Chenodiol, doses that are too low are associated with increased cholecystectomy rates (see ADVERSE REACTIONS).

Stones have recurred within five years in about 50% of patients following complete confirmed dissolutions. Although retreatment with Chenodiol has proven successful in dissolving some newly formed stones, the indications for and safety of retreatment are not well defined. Serum aminotransferase elevations and diarrhea have been notable in all clinical trials and are dose-related (refer to ADVERSE REACTIONS and WARNINGSsections for full information).

Floatable versus Nonfloatable Stones; A major finding in clinical trials was a difference between floatable and nonfloatable stones, with respect to both natural history and response to Chenodiol. Over the two-year course of the National Cooperative Gallstone Study (NCGS), placebo – treated patients with floatable stones (n = 47) had significantly higher rates of biliary pain and cholecystectomy than patients with nonfloatable stones (n = 258) (47% versus 27% and 19%versus 4%, respectively). Chenodiol treatment (750 mg/day) compared to placebo was associated with a significant reduction in both biliary pain and the cholecystectomy rates in the group with floatable stones (27% versus 47% and 1.5% versus 19%, respectively). In an uncontrolled clinical trial using 15 mg/kg/day, 70% of the patients with small (less than 15 mm) floatable stones (n = 10) had complete confirmed dissolution.

In the NCGS in patients with nonfloatable stones, Chenodiol produced no reduction in biliary pain and showed a tendency to increase the cholecystectomy rate (8% versus 4%). This finding was more pronounced with doses of Chenodiol below 10 mg/kg. The subgroup of patients with nonfloatable stones and a history of biliary pain had the highest rates of cholecystectomy and aminotransferase elevations during Chenodiol treatment. Except for the NCGS subgroup with pretreatment biliary pain, dose-related aminotransferase elevations and diarrhea have occurred with equal frequency in patients with floatable or nonfloatable stones. In the uncontrolled clinical trial mentioned above, 27% of the patients with nonfloatable stones (n = 59) had complete confirmed dissolutions, including 35% with small (less than 15 mm)(n= 40) and only 11% with large, nonfloatable stones (n= 19).

Of 916 patients enrolled NCGS, 17.6% had stones seen in upright form (horizontal X-ray beam) to float in the dye-laden bile during oral cholecystography using iopanoic acid. Other investigators report similar findings. Floatable stones are not detected by ultrasonography in the absence for dye. Chemical analysis has shown floatable stones to be essentially pure cholesterol).

Other Radiographic and Laboratory Features: Radiolucent stones may have rims or centers of opacity representing calcification. Pigment stones and partially calcified radiolucent stones do not respond to Chenodiol. Subtle calcification can sometimes be detected in flat film X-rays, if not obvious in the oral cholecystogram. Among nonfloatable stones, cholesterol stones are more apt than pigment stones to be smooth surfaced, less than 0.5 cm in diameter, and to occur in numbers less than 10. As stone size number and volume increase, the probability of dissolution within 24 months decreases. Hemolytic disorders, chronic alcoholism, biliary cirrhosis and bacterial invasion of the biliary system predispose to pigment gallstone formation. Pigment stones of primary biliary cirrhosis should be suspected in patients with elevated alkaline phosphates, especially if positive anti-mitochondrial antibodies are present. The presence of microscopic cholesterol crystals in aspirated gallbladder bile, and demonstration of cholesterol super saturation by bile lipid analysis increase the likelihood that the stones are cholesterol stones.

PATIENT SELECTION

Evaluation of Surgical Risk; Surgery offers the advantage of immediate and permanent stone removal, but carries a fairly high risk. In some patients. About 5% of cholecystectomized patients have residual symptoms or retained common duct stones. The spectrum to surgical risk varies as a function of age and the presence of disease other than cholelithiasis. Selected tabulation of results from the National Halothane Study (JAMA, 1968, 197:775-778) is shown below: the study included 27,600 cholecystectomies.

Mortality per Operation (Smoothed rates with denominators adjusted to one death)

* Includes those with good health or moderate systemic disease, with or without emergency surgery. ** Severe or extreme systemic disease, with or with-out emergency surgery.
Low Risk Patients*		Cholecystectomy	Cholecystectomy & Common Duct Exploration
Women	0-49 yrs	1/1851	1/469
	50-69 yrs	1/357	1/99
Men	0-49 yrs	1/981	1/243
	50-69 yrs	1/185	1/52
High Risk Patients**
Women	0-49 yrs	1/79	1/21
	50-69 yrs	1/56	1/17
Men	0-49 yrs	1/41	1/11
	50-69 yrs	1/30	1/9

 Women in good health, or having only moderate systemic disease, under 49 years of age have the lowest rate (0.054%); men in all categories have a surgical mortality rate twice that of women; common duct exploration quadruples the rates in all categories; the rates rise with each decade of life and increase tenfold or more in all categories with severe or extreme systemic disease.

Relatively young patients requiring treatment might be better treated by surgery than with Chenodiol, because treatment with Chenodiol, even if successful, is associated with a high rate of recurrence, The long-term consequences of repeated courses of Chenodiol in terms of liver toxicity, neoplasia and elevated cholesterol levels are not know.

Watchful waiting has the advantage that no therapy may ever be required. For patients with silent or minimally symptomatic stones, the rate of moderate to severe symptoms or gallstone complications is estimated to be between 2% and 6% per year, leading to a cumulative rate of 7% and 27%in five years. Presumably the rate is higher for patients already having symptoms.

INDICATIONS AND USAGE

Chenodiol is indicated for patients with radiolucent stones in well-opacifying gallbladders, in whom selective surgery would be undertaken except for the presence of increased surgical risk due to systemic disease or age. The likelihood of successful dissolution is far greater if the stones are floatable or small. For patients with nonfloatable stones, dissolution is less likely and added weight should be given to the risk that more emergent surgery might result form a delay due to unsuccessful treatment. Safety of use beyond 24 months is not established. Chenodiol will not dissolve calcified (radiopaque) or radiolucent bile pigment stones.

CONTRAINDICATIONS

Chenodiol is contraindicated in the presence of know hepatocyte dysfunction or bile ductal abnormalities such as intrahepatic cholestasis, primary biliary cirrhosis or sclerosing cholangitits (see Warnings); a gallbladder confirmed as nonvisualizing after two consecutive single doses of dye; radiopaque stones; or gallstone complications or compelling reasons for gallbladder surgery including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary gastrointestinal fistula.

Pregnancy Category X:

Chenodiol may cause fetal harm when administered to a pregnant woman. Serious hepatic, renal and adrenal lesions occurred in fetuses of female Rhesus monkeys given 60 to 90 mg/kg/day (4 to 6 times the maximum recommended human dose, MRHD) from day 21 to day 45 of pregnancy. Hepatic lesions also occurred in neonatal baboons whose mothers had received 18 to 38 mg/kg ( 1 to 2 times the MRHD), all during pregnancy. Fetal malformations were not observed. Neither fetal liver damage nor fetal abnormalities occurred in reproduction studies in rats and hamsters. No human data are available at this time. Chenodiol is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

WARNINGS

Safe use of Chenodiol depends upon selection of patients without pre-existing liver disease and upon faithful monitoring of serum aminotransferase levels to detect drug-induced liver toxicity. Aminotransferase elevations over three times the upper limit of normal have required discontinuation of Chenodiol in 2% to 3% of patients. Although clinical and biopsy studies have not shown fulminant lesions, the possibility remains that an occasional patient may develop serious hepatic disease. Three patients with biochemical and histologic pictures of chronic active hepatitis while on Chenodiol, 375 mg/day or 750 mg/day, have been reported. The biochemical abnormalities returned spontaneously to normal in two of the patients within 13 and 17 months; and after 17 months’ treatment with prednisone in the third. Follow-up biopsies were not done; and the causal relationship of the drug could not be determined. Another biopsied patient was terminated from therapy because of elevated aminotransferase levels and a liver biopsy was interpreted as showing active drug hepatitis.

One patient with sclerosing cholangitis, biliary cirrhosis and history of jaundice died during Chenodiol treatment for hepatic duct stones. Before treatment, serum aminotransferase and alkaline phosphate levels were over twice the upper limit of normal; within one month they rose to over 10 time normal. Chenodiol was discontinued at seven weeks, when the patient was hospitalized with advanced hepatic failure and E. coli peritonitis; death ensued at the eight week. A contribution of Chenodiol to the fatal outcome could not be ruled out.

Epidemiologic studies suggest that bile acids might contribute to human colon cancer, but direct evidence is lacking. Bile acids, including Chenodiol and lithocholic acid, have no carcinogenic potential in animal models, but have been shown to increase the number of tumors when administered with certain know carcinogens. The possibility that Chenodiol therapy might contribute to colon cancer in otherwise susceptible individuals cannot be ruled out.

PRECAUTIONS

Information for patients

Patients should be counseled on the importance of periodic visits for liver function tests and oral cholecystograms (or ultrasonograms) for monitoring stone dissolution; they should be made aware of the symptoms of gallstone complications and be warned to report immediately such symptoms to the physician. Patients should be instructed on ways to facilitate faithful compliance with the dosage regimen throughout the usual long term of therapy, and on temporary doses reduction if episodes of diarrhea occur.

Drug interactions

Bile acid sequestering agents, such as cholestyramine and colestipol, may interfere with the action of Chenodiol by reducing its absorption. Aluminum-based antacids have been shown to absorb bile acids in vitro and may be expected to interfere with Chenodiol in the same manner as the sequestering agents. Estrogen, oral contraceptive and collaborate (and perhaps other lipid-lowering drugs) increase biliary cholesterol secretion, and the incidence of cholesterol gallstones hence may counteract the effectiveness of Chenodiol.

Due to its hepatotoxicity, Chenodiol can affect the pharmacodynamics of coumarin and its derivatives, causing unexpected prolongation of the prothrombin time and hemorrahages. Patients on concommitant therapy with Chenodiol and coumarin or its derivatives should be monitored carefully. If prolongation of prothrombin time is observed, the coumarin dosage should be readjusted to give a prothrombin time 1½ to 2 times normal. If necessary Chenodiol should be discontinued.

Carcinogenesis, mutagenesis, impairment of fertility

A two-year oral study of Chenodiol in rats failed to show a carcinogenic potential at the tested levels of 15 to 60 mg/kg/day (1 to 4 times the maximum recommended human dose, MRHD). It has been reported that Chenodiol given in long-term studies at oral doses up to 600 mg/kg/day (40 times the MRHD) to rats and 1000 mg/kg/day (65 times the MRHD) to mice induced benign and malignant liver cell tumors in female rats and cholangiomata in female rats and male mice. Two-year studies of lithocholic acid ( a major metabolite of Chenodiol) in mice (125 to 250 mg/kg/day) and rats (250 and 500 mg/kg/day) found it not to be carcinogenic. The dietary administration of Lithocholic acid to chickens is reported to cause hepatic adenomatous hyperplasia.

Pregnancy

Pregnancy Category X: See CONTRAINDICATIONS.

Nursing mothers

It is not known whether Chenodiol is excreted in human mild. Because many drugs are excreted in human milk, caution should be exercised when Chenodiol is administered to a nursing mother.

Pediatric use

The safety and effectiveness of Chenodiol in children have not been established.

ADVERSE REACTIONS

Hepatobiliary: Dose-related serum aminotransferase (mainly SGPT) elevations, usually not accompanied by rises in alkaline phosphatase or bilirubin, occurred in 30% or more of patients treated with the recommended dose of Chenodiol. In most cases, these elevations were minor (1 ½ to 3 times the upper limit of laboratory normal) and transient, returning to within the normal range within six months despite continued administration of the drug. In 2% to 3% of patients, SGPT levels rose to over three times the upper limit of laboratory normal, recurred on rechallenge with the drug, and required discontinuation of Chenodiol treatment. Enzyme levels have returned to normal following withdrawal of Chenodiol (see WARNINGS).

Morphologic studies of liver biopsies taken before and after 9 and 24 months of treatment with Chenodiol have shown that 63% of the patients prior to Chenodiol treatment had evidence of intrahepatic cholestasis. Almost all pretreatment patients had electron microscopic abnormalities. By the ninth month of treatment, reexamination of two-thirds of the patients showed an 89% incidence of the signs of intrahepatic cholestasis. Two of 89 patients at the ninth month had lithocholate-like lesions in the canalicular membrane, although there were not clinical enzyme abnormalities in the face of continued treatment and no change in Type 2 light microscopic parameters.

Increased Cholecystectomy Rate: NCGS patients with a history of biliary pain prior to treatment had higher cholecystectomy rates during the study if assigned to low dosage Chenodiol (375 mg/day) than if assigned to either placebo or high dosage Chenodiol (750 mg/day). The association with low dosage Chenodiol though not clearly a causal one, suggests that patients unable to take higher doses of Chenodiol may be at greater risk of cholecystectomy.

Gastrointestinal: Dose-related diarrhea has been encountered in 30% to 40% of Chenodiol-treated patients and may occur at any time during treatment, but is most commonly encountered when treatment is initiated. Usually, the diarrhea is mild, translucent, well-tolerated and does not interfere with therapy. Dose reduction has been required in 10% to 15% of patients, and in a controlled trial about half of these required a permanent reduction in dose. Anti-diarrhea agents have proven useful in some patients.

Discontinuation of Chenodiol because of failure to control diarrhea is to be expected in approximately 3% of patients treated. Steady epigastric pain with nausea typical of lithiasis (biliary colic) usually is easily distinguishable from the crampy abdominal pain of drug-induced diarrhea.

Other less frequent, gastrointestinal side effects reported include urgency, cramps, heartburn, constipation, nausea, and vomiting, anorexic, epigastric distress, dyspepsis, flatulence and nonspecific abdominal pain.

Serum Lipids: Serum total cholesterol and low-density lipoprotein (LDL) cholesterol may rise 10% or more during administration of Chenodiol: no change has been seen in the high-density lipoprotein (HDL) fraction; small decreases in serum triglyceride levels for females have been reported.

Hematologic: Decreases in white cell count, never below 3000, have been noted in a few patients treated with Chenodiol; the drug was continued in all patients without incident.

DRUG ABUSE AND DEPENDENCE

Overdosage

Accidental or intentional overdoses of Chenodiol have not been reported. One patient tolerated 4 gm/day (58 mg/kg/day) for six months without incident.

DOSAGE AND ADMINISTRATION

The recommended dose range for Chenodiol is 13 to 16 mg/kg/day in two divided doses, morning and night, starting with 250 mg b.i.d. the first two weeks and increasing by 250 mg/day each week thereafter until the recommended or maximum tolerated dose is reached. If diarrhea occurs during dosage buildup or later in treatment, it usually can be controlled by temporary dosage adjustment until symptoms abate, after which the previous dosage usually is tolerated. Dosage less than 10 mg/kg usually is ineffective and may be associated with increased risk of cholecystectomy, so is not recommended.

Weight/Dosage Guide

Body Weight		Recommended Tablets/Day	Dose Range mg/kg
lb	kg
100-130	45-58	3	17-13
131-185	59-75	4	17-13
186-200	76-90	5	18-14
201-235	91-107	6	18-14
236-275	108-125	7	18-14

The optimal frequency of monitoring liver function tests is not known. It is suggested that serum aminotransferase levels should be monitored monthly for the first three months and every three months thereafter during Chenodiol administration. Under NCGS guidelines, if a minor, usually transient elevations (1 ½ to3 three times the upper limit of normal) persisted longer than three to six months. Chenodiol was discontinued and resumed only after the aminotransferase level returned to normal; however, allowing the elevations to persist over such an interval is not know to be safe. Elevations over three times the upper limit of normal require immediate discontinuation of Chenodiol and usually reoccur on challenge.

Serum cholesterol should be monitored at six months intervals. It may be advisable to discontinue Chenodiol if cholesterol rises above the acceptable age-adjusted limit for given patient.

Oral cholecystograms or ultrasonograms are recommend at six to nine month intervals to monitor response. Complete dissolutions should be confirmed by a repeat test after one to three months continued Chenodiol administration. Most patients who eventually achieve complete dissolution will show partial (or complete) dissolution at the first on-treatment test. If partial dissolution is not seen by nine to 12 months, the likelihood of success of treating loner is greatly reduced; Chenodiol should be discontinued if there is no response by 18 months. Safety of use beyond 24 months is not established.

Stone recurrence can be expected within five years in 50% of cases. After confirmed dissolution, treatment generally should be stopped. Serial cholecystograms or ultrasonograms are recommended to monitor for recurrence, keeping in mind that radiolucency and gallbladder function should be established before starting another course of Chenodiol. A prophylactic doses is not established; reduced doses cannot be recommended; stones have recurred on 500 mg/day. Low cholesterol or carbohydrate diets, and dietary bran, have been reported to reduce biliary cholesterol; maintenance of reduced weight is recommended to forestall stone recurrence.

HOW SUPPLIED

Chenodiol is available as white film-coated 250 mg tablets imprinted “MP” on one side and "250" on the other in bottles of 100, NDC 0722-7121-01.

Store at 20oC to 25oC (68oF to 77oF) [see USP Controlled Room Temperature].

Dispense in a tight container.

Manufactured by:

Nexgen Pharma, Inc.

Irvine, CA 92614-6502

Rev. 08/09

CARTON LABEL

Chenodiol Carton Label

Chenodiol  Chenodiol  tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0722-7121 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Chenodiol (Chenodiol) Chenodiol 250 mg

Inactive Ingredients Ingredient Name Strength MAGNESIUM STEARATE 6 mg CELLULOSE, MICROCRYSTALLINE 50 mg METHYLCELLULOSE (100 CPS) 3.8 mg STARCH, CORN 125 mg SILICON DIOXIDE 6 mg SODIUM LAURYL SULFATE 0.82 mg SODIUM STARCH GLYCOLATE TYPE A POTATO 17 mg GLYCERIN 0.3 mg

Product Characteristics Color WHITE (White to Off-White) Score no score Shape ROUND Size 10mm Flavor Imprint Code MP;250 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0722-7121-01 1 CONTAINER In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA091019	10/01/2009

Labeler - Nexgen Pharma, Inc. (048488621)

Revised: 08/2009Nexgen Pharma, Inc.

More Chenodiol resources

• Chenodiol Use in Pregnancy & Breastfeeding
• Chenodiol Drug Interactions
• Chenodiol Support Group
• 0 Reviews for Chenodiol - Add your own review/rating

Compare Chenodiol with other medications

• Gallbladder Disease

chamomile

Generic Name: chamomile (KAH moe meal)

Brand Names:

What is chamomile?

The use of chamomile in cultural and traditional settings may differ from concepts accepted by current Western medicine. When considering the use of herbal supplements, consultation with a primary health care professional is advisable. Additionally, consultation with a practitioner trained in the uses of herbal/health supplements may be beneficial, and coordination of treatment among all health care providers involved may be advantageous.

Two plants each provide the product known as chamomile. Matricaria chamomilla is also known as German chamomile, Hungarian chamomile, pin heads, chamomilla, wild chamomile, sweet false chamomile, and genuine chamomile. Anthemis nobilis is also known as English or Roman chamomile, ground apple, whig plant, and common chamomile.

Chamomile has been used orally to reduce flatulence and/or diarrhea due to a nervous stomach, to reduce stomach upset, to treat travel sickness, to produce mild sedation, to reduce restlessness and irritability, to treat the common cold, to treat fevers, to reduce cough, for liver and gallbladder complaints, and to increase appetite. Chamomile has also been used topically to reduce inflammation of the skin, mouth, and throat; to reduce nasal inflammation and discharge; and to treat wounds and burns.

Chamomile has not been evaluated by the FDA for safety, effectiveness, or purity. All potential risks and/or advantages of chamomile may not be known. Additionally, there are no regulated manufacturing standards in place for these compounds. There have been instances where herbal/health supplements have been sold which were contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.

Chamomile may also have uses other than those listed in this product guide.

What is the most important information I should know about chamomile?

Do not take chamomile without first talking to your doctor if you are taking warfarin (Coumadin) or another blood thinner. You may not be able to take chamomile, or you may require special monitoring during treatment if you are taking a blood thinner.

Talk to your doctor before taking or using chamomile if you have any other medical conditions, allergies (especially to ragweed, asters, chrysanthemums, celery, or other plants), or if you take other medicines. Chamomile may not be recommended in some situations.

Chamomile has not been evaluated by the FDA for safety, effectiveness, or purity. All potential risks and/or advantages of chamomile may not be known. Additionally, there are no regulated manufacturing standards in place for these compounds. There have been instances where herbal/health supplements have been sold which were contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.

Who should not take chamomile?

Do not take chamomile without first talking to your doctor if you are taking warfarin (Coumadin) or another blood thinner. You may not be able to take chamomile, or you may require special monitoring during treatment if you are taking a blood thinner.

Talk to your doctor before taking chamomile if you have any other medical conditions, allergies (especially to ragweed, asters, chrysanthemums, celery, or other plants), or if you take other medicines or herbal/health supplements. Chamomile may not be recommended in some situations.

Do not take chamomile without first talking to your doctor if you are pregnant or could become pregnant. It is not known whether chamomile will harm an unborn baby. Do not take chamomile without first talking to your doctor if you are breast-feeding a baby. It is also not known whether chamomile will harm a nursing infant. There is no information available regarding the use of chamomile by children. Do not give any herbal/health supplement to a child without first talking to the child's doctor.

How should I take chamomile?

The use of chamomile in cultural and traditional settings may differ from concepts accepted by current Western medicine. When considering the use of herbal supplements, consultation with a primary health care professional is advisable. Additionally, consultation with a practitioner trained in the uses of herbal/health supplements may be beneficial, and coordination of treatment among all health care providers involved may be advantageous.

If you choose to use chamomile, use it as directed on the package or as directed by your doctor, pharmacist, or other health care provider.

Standardized extracts, tinctures, and solid formulations of herbal/health supplements may provide a more reliable dose of the product.

Chamomile is available in pill and liquid formulations. Other formulations may also be available.

Some forms of chamomile are intended for internal (oral) use while others are intended for external (topical) use.

Do not take more of this product than is directed. Do not use different formulations (e.g., tablets, topical formulations, teas, tinctures, and others) of chamomile at the same time, unless specifically directed to do so by a health care professional. Using different formulations together increases the risk of an overdose of chamomile.

Store chamomile as directed on the package. In general, chamomile should be protected from light and moisture. The Anthemis nobilis form of chamomile should be stored in a well-sealed glass or metal container.

What happens if I miss a dose?

Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra chamomile to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking chamomile?

Follow your healthcare provider's instructions about any restrictions on food, beverages, or activity.

Chamomile side effects

Although uncommon, serious side effects have been reported with the use of chamomile. Stop taking chamomile and seek emergency medical attention or notify your doctor immediately if you experience:

• 
  

  an allergic reaction (difficulty breathing; closing of your throat; swelling of your lips, tongue, or face; or hives); or

  
  


• 
  

  vomiting.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect chamomile?

Do not take chamomile without first talking to your doctor if you are taking

• 
  

  warfarin (Coumadin),

  
  


• 
  

  ardeparin (Normiflo),

  
  


• 
  

  dalteparin (Fragmin),

  
  


• 
  

  danaparoid (Orgaran),

  
  


• 
  

  enoxaparin (Lovenox),

  
  


• 
  

  heparin, or

  
  


• 
  

  another blood thinner.

  
  

You may not be able to take chamomile, or you may require a dosage adjustment or special monitoring during treatment if you are taking any of the medicine listed above.

Drugs other than those listed here may also interact with chamomile. Talk to your doctor, pharmacist, or health care provider before taking any prescription or over-the-counter medicines or other herbal/health supplements.

More chamomile resources

• Chamomile Side Effects (in more detail)
• Chamomile Use in Pregnancy & Breastfeeding
• Chamomile Drug Interactions
• Chamomile Support Group
• 0 Reviews for Chamomile - Add your own review/rating

• Chamomile Natural MedFacts for Professionals (Wolters Kluwer)


• Chamomile Natural MedFacts for Consumers (Wolters Kluwer)


• Chamomile MedFacts Consumer Leaflet (Wolters Kluwer)

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• Burns, External
• Diarrhea
• Fever
• Gas
• Herbal Supplementation
• Infectious Gastroenteritis
• Motion Sickness
• Nasal Congestion
• Sedation
• Skin Rash
• Upper Respiratory Tract Infection

Where can I get more information?

• Consult with a licensed healthcare professional before using any herbal/health supplement. Whether you are treated by a medical doctor or a practitioner trained in the use of natural medicines/supplements, make sure all your healthcare providers know about all of your medical conditions and treatments.

See also: chamomile side effects (in more detail)

Ciprofloxacin Injection Concentrate

Ciprofloxacin Injection, USP (1% w/v)

and

Ciprofloxacin in Dextrose (5%) Injection, USP

(ciprofloxacin)

For Intravenous Infusion

WARNING

Fluoroquinolones, including Ciprofloxacin Injection, USP, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. (See WARNINGS).

Fluoroquinolones, including Ciprofloxacin Injection, USP, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid Ciprofloxacin Injection, USP in patients with known history of myasthenia gravis(See WARNINGS).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ciprofloxacin Injection, USP and other antibacterial drugs, Ciprofloxacin Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Ciprofloxacin Injection Concentrate Description

Ciprofloxacin Injection USP (ciprofloxacin) is a synthetic broad-spectrum antimicrobial agent for intravenous (I.V.) administration. Ciprofloxacin, a fluoroquinolone, is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its chemical structure is:

Ciprofloxacin is a faint to light yellow crystalline powder with a molecular weight of 331.4. It is soluble in dilute (0.1N) hydrochloric acid and is practically insoluble in water and ethanol. Ciprofloxacin Injection, USP solutions are available as sterile 1.0% aqueous concentrates, which are intended for dilution prior to administration, and as 0.2% ready-for-use infusion solutions in 5% Dextrose Injection. All formulas contain lactic acid as a solubilizing agent and hydrochloric acid for pH adjustment. The pH range for the 1.0% aqueous concentrates in vials is 3.3 to 3.9. The pH range for the 0.2% ready-for-use infusion solutions is 3.5 to 4.6.

The plastic container is fabricated from a specially formulated polyvinyl chloride. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di(2-ethylhexyl) phthalate (DEHP), up to 5 parts per million. The suitability of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers.

Ciprofloxacin Injection Concentrate - Clinical Pharmacology

Absorption

Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers, the mean maximum serum concentrations achieved were 2.1 and 4.6 µg/mL, respectively; the concentrations at 12 hours were 0.1 and 0.2 µg/mL, respectively.

Steady-state Ciprofloxacin Serum Concentrations (µg/mL) After 60-minute I.V. Infusions q12 h.
		Time after starting the infusion
Dose	30 min.	1 hr	3 hr	6 hr	8 hr	12 hr
200 mg	1.7	2.1	0.6	0.3	0.2	0.1
400 mg	3.7	4.6	1.3	0.7	0.5	0.2

The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q 12 h regimen indicates no evidence of drug accumulation. The absolute bioavailability of oral ciprofloxacin is within a range of 70-80% with no substantial loss by first pass metabolism. An intravenous infusion of 400-mg ciprofloxacin given over 60 minutes every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V. dose results in a Cmax similar to that observed with a 750-mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.

* AUC0-12h † AUC 24h=AUC0-12h x 2 ‡ AUC 24h=AUC0-8h x 3
Steady-state Pharmacokinetic Parameter Following Multiple Oral and I.V. Doses
Parameters	500 mg q12h, P.O.	400 mg q12h, I.V.	750 mg q12h, P.O.	400 mg q8h, I.V.
AUC (µg•hr/mL)	13.7*	12.7*	31.6†	32.9‡
Cmax (µg/mL)	2.97	4.56	3.59	4.07

Distribution

After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are lower than in serum.

Metabolism

After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration 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 coadministered drug (see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions.)

Excretion

The serum elimination half-life is approximately 5-6 hours and the total clearance is around 35 L/hr. After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 µg/mL 0-2 hours after dosing and are generally greater than 15 µg/mL 8-12 hours after dosing. Following a 400-mg I.V. dose, urine concentrations generally exceed 400 µg/mL 0-2 hours after dosing and are usually greater than 30 µg/mL 8-12 hours after dosing. The renal clearance is approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing.

Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after intravenous dosing, only a small amount of the administered dose (< 1%) is recovered from the bile as unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after dosing.

Special Populations

Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16-40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.)

In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage adjustments may be required. (See DOSAGE AND ADMINISTRATION.) In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients with acute hepatic insufficiency have not been fully elucidated. Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4 months to 7 years, the mean Cmax was 2.4 µg/mL (range: 1.5 to 3.4 µg/mL) and the mean AUC was 9.2 µg•h/mL (range: 5.8 to 14.9 µg•h/mL). There was no apparent age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 µg/mL (range: 4.6 to 8.3 µg/mL) in 10 children less than 1 year of age; and 7.2 µg/mL (range: 4.7 to 11.8 µg/mL) in 10 children between 1 and 5 years of age. The AUC values were 17.4 µg•h/mL (range: 11.8 to 32 µg•h/mL) and 16.5 µg•h/mL (range: 11 to 23.8 µg•h/mL) in the respective age groups. These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.

Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated. (See CONTRAINDICATIONS). The potential for pharmacokinetic drug interactions between ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. (See WARNINGS; PRECAUTIONS: Drug Interactions.)

MICROBIOLOGY

Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations.

Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.

Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for Ciprofloxacin Injection, USP (ciprofloxacin for intravenous infusion).

Aerobic gram-positive microorganisms

Enterococcus faecalis (Many strains are only moderately susceptible.)

Staphylococcus aureus (methicillin-susceptible strains only)

Staphylococcus epidermidis (methicillin-susceptible strains only)

Staphylococcus saprophyticus

Streptococcus pneumoniae (penicillin-susceptible strains)

Streptococcus pyogenes

Aerobic gram-negative microorganisms

Citrobacter diversus                            Morganella morganii

Citrobacter freundii                             Proteus mirabilis

Enterobacter cloacae                        Proteus vulgaris

Escherichia coli                                 Providencia rettgeri

Haemophilus influenzae                  Providencia stuartii

Haemophilus parainfluenzae          Pseudomonas aeruginosa

Klebsiella pneumoniae                    Serratia marcescens

Moraxella catarrhalis

Ciprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as a surrogate marker. (See INDICATIONS AND USAGE and INHALATIONAL ANTHRAX — ADDITIONAL INFORMATION). The following in vitro data are available, but their clinical significance is unknown.

Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 µg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of ciprofloxacin intravenous formulations in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

Staphylococcus haemolyticus

Staphylococcus hominis

Streptococcus pneumoniae (penicillin-resistant strains)

Aerobic gram-negative microorganisms

Acinetobacter iwoffi                        Salmonella typhi

Aeromonas hydrophila                  Shigella boydii

Campylobacter jejuni                    Shigella dysenteriae

Edwardsiella tarda                       Shigella flexneri

Enterobacter aerogenes             Shigella sonnei

Klebsiella oxytoca                       Vibrio cholerae

Legionella pneumophila             Vibrio parahaemolyticus

Neisseria gonorrhoeae              Vibrio vulnificus

Pasteurella multocida                Yersinia enterocolitica

Salmonella enteritidis

Most strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method 1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas aeruginosa*:

* These interpretive standards are applicable only to broth microdilution susceptibility tests with streptococci using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.
MIC (µg/mL)	Interpretation
≤ 1	Susceptible (S)
2	Intermediate (I)
≥ 4	Resistant (R)

For testing Haemophilus influenzae and Haemophilus parainfluenzae*:

* This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.
MIC (µg/mL)	Interpretation
≤ 1	Susceptible (S)

The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding MIC results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide the following MIC values:

* This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM)1.
Organism		MIC (µg/mL)
E. faecalis	ATCC 29212	0.25 -2.0
E. coli	ATCC 25922	0.004 -0.015
H. influenzae*	ATCC 49247	0.004 -0.03
P. aeruginosa	ATCC 27853	0.25 -1.0
S. aureus	ATCC 29213	0.12 -0.5

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-µg ciprofloxacin to test the susceptibility of microorganisms to ciprofloxacin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-µg ciprofloxacin disk should be interpreted according to the following criteria:

For testing Enterobacteriaceae, Enter ococcusfaecalis, methicillin-susceptible Staphylococcus species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas aeruginosa*:

* These zone diameter standards are applicable only to tests performed for streptococci using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2
Zone Diameter (mm)	Interpretation
≥ 21	Susceptible (S)
16 - 20	Intermediate (I)
≤ 15	Resistant (R)

For testing Haemophilus influenzae and Haemophilus parainfluenzae*:

* This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.
Zone Diameter (mm)	Interpretation
≥ 21	Susceptible (S)

The current absence of data on resistant strains precludes defining any results other than “Susceptible”. Strains yielding zone diameter results suggestive of a “nonsusceptible” category should be submitted to a reference laboratory for further testing.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-µg ciprofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:

* These quality control limits are applicable to only H. influenzae ATCC 49247 testing using Haemophilus Test Medium (HTM)2.
Organism		Zone Diameter (mm)
E. coli	ATCC 25922	30 - 40
H. influenzae*	ATCC 49247	34 - 42
P. aeruginosa	ATCC 27853	25 - 33
S. aureus	ATCC 25923	22 - 30

Indications and Usage for Ciprofloxacin Injection Concentrate

Ciprofloxacin Injection, USP is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions and patient populations listed below when the intravenous administration offers a route of administration advantageous to the patient. Please see DOSAGE AND ADMINISTRATION for specific recommendations.

Adult Patients:

Urinary Tract Infections caused by Escherichia coli (including cases with secondary bacteremia), Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus faecalis.

Lower Respiratory Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae. Also, Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.

NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.

Nosocomial Pneumonia caused by Haemophilus influenzae or Klebsiella pneumoniae.

Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae subspecies pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillinsusceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes.

Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa.

Complicated Intra-Abdominal Infections (used in conjunction with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.

Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae, or Moraxella catarrhalis.

Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.

Empirical Therapy for Febrile Neutropenic Patients in combination with piperacillin sodium. (See CLINICAL STUDIES.)

Pediatric Patients (1 to 17 years of age):

Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.

NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues. (See WARNINGS, PRECAUTIONS: Pediatric Use, ADVERSE REACTIONS and CLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL PHARMACOLOGY.)

Adult and Pediatric Patients:

Inhalational Anthrax (post-exposure): To reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.

Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for this indication.4 Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October 2001.(See also, INHALATIONAL ANTHRAX — ADDITIONAL INFORMATION).

If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered.

Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with Ciprofloxacin Injection, USP may be initiated before results of these tests are known; once results become available, appropriate therapy should be continued.

As with other drugs, some strains of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ciprofloxacin Injection, USP and other antibacterial drugs, Ciprofloxacin Injection, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Contraindications

Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components.

Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug Interactions.)

Warnings

Tendinopathy and Tendon Rupture:Fluoroquinolones, including Ciprofloxacin injection, USP are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Ciprofloxacin Injection, USP should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.

Exacerbation of Myasthenia Gravis: Fluoroquinolones, including Ciprofloxacin Injection, USP, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid Ciprofloxacin Injection, USP in patients with known history of myasthenia gravis. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS: Post-Marketing Adverse Event Reports.)

Pregnant Women: THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)

Pediatrics: Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed.(See ADVERSE REACTIONS.)

In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. (See ANIMAL PHARMACOLOGY.)

Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g. theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug.

Central Nervous System Disorders: Convulsions, increased intracranial pressure and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interaction and ADVERSE REACTIONS.)

Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse events have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.

Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including ciprofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

• 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.

The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted (See PRECAUTIONS: General, Information for Patients and ADVERSE REACTIONS).

Pseudomembranous Colitis: Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ciprofloxacin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Peripheral Neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.

Precautions

General

IINTRAVENOUS CIPROFLOXACIN SHOULD BE ADMINISTERED BY SLOW INFUSION OVER A PERIOD OF 60 MINUTES. Local I.V. site reactions have been reported with the intravenous administration of ciprofloxacin. These reactions are more frequent if infusion time is 30 minutes or less or if small veins of the hand are used. (See ADVERSE REACTIONS.)

Central Nervous System

Quinolones, including ciprofloxacin, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS, Information for Patients, and Drug Interaction.)

Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.

Renal Impairment

Alteration of the dosage regimen is necessary for patients with impairment of renal function. (See DOSAGE AND ADMINISTRATION.)

Photosensitivity/Phototoxicity

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, "V" area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (See and ADVERSE REACTIONS/ Post-Marketing Adverse Events).

As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Prescribing Ciprofloxacin Injection, USP in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information For Patients

Patients should be advised:

• 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 Injection, USP 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 Injection, USP 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 Injection, USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Ciprofloxacin Injection, USP is 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 Injection, USP or other antibacterial drugs in the future.


• 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 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 (Zanaflex®). 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 ciprofloxacin.


• 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 convulsions have been reported in patients taking 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 and ADVERSE REACTIONS.)


• that diarrhea is a common problem caused by antibiotics which usually ends whe