All brand names are trademarks of their respected manufacturers.  The information being provided below is to be considered a quick reference guide.  For complete information please view the complete package insert at www.rxlist.com or by entering the drug name at Drugs@FDA
 

QUINOLONES MAY HAVE THE POTENTIAL TO PROLONG THE QTc INTERVAL OF THE ELECTROCARDIOGRAM IN SOME PATIENTS. DUE TO THE LACK OF CLINICAL EXPERIENCE, GATIFLOXACIN SHOULD BE AVOIDED IN PATIENTS WITH KNOWN PROLONGATION OF THE QTc INTERVAL, PATIENTS WITH UNCORRECTED HYPOKALEMIA, AND PATIENTS RECEIVING CLASS IA (E.G. QUINIDINE, PROCAINAMIDE) OR CLASS III (E.G. AMIODARONE, SOTALOL) ANTIARRHYTHMIC AGENTS.

Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Tendon rupture can occur during or after therapy with quinolones.

Quinolones may cause central nervous system (CNS) events including nervousness, agitation, insomnia, anxiety, nightmares, or paranoia.

As with other quinolones, disturbances of blood glucose, including symptomatic hyper- and hypoglycemia, have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycemic (e. g., glyburide) or with insulin. In these patients, the monitoring of blood glucose is recommended.

Trovafloxacin

Brand Names: Trovan

Public Citizen list this drug as DO NOT USE

Do Not Use
Generic drug name: trovafloxacin (troe va FLOX a sin)
Brand name(s): TROVAN (Pfizer)
FAMILY: Fluoroquinolones

Removed from clinical use due to severe toxicity (ie:hepatic reactions)

TROVAFLOXACIN MESYLATE
CP-99219-27
Scientific and common names, and synonyms
C.A.S. number 147059-72-1

Legislative or regulation action

USA The Food and Drug Administration has restricted the indications for products containing
trovafloxacin or alatrofloxacin to patients having nosocomial infections or complicated intra-
abdominal infections that are serious or life- threatening. This is due to concerns over the
risks of serious liver toxicity.
(Reference: (FDATP) Food and Drug Administration Talk Paper, T99-26, , June 1999)

SGP The National Pharmaceutical Administration in the Ministry of Health has not approved
trovafloxacin since it is associated with hepatic adverse reactions.
(Reference: (SGPCW) Communication to WHO, , , 02 Aug 2000)

PHL Jan 2000 The Department of Health Bureau of Food and Drugs have banned and withdrawn
trovafloxacin since it is associated with hepatic adverse reactions.
(Reference: (PHADO) Administrative Order, (1) s. 2000, , 03 Jan 2000)

VTN Jul 1999 The Drug Administration of Viet Nam in the Ministry of Health has not approved the
registration of trovafloxacin (Trovan) solution for injection 5 mg/ml and tablet 200 mg on the
basis that these products have a potential for hepatotoxicity.
(Reference: (VTNMHD) Directive, 2785, QLD, 15 July 1999)

MAR Jun 1999 The National Advisory Commission for Pharmacovigilance has decided to restrict the use of trovafloxacin and alatrofloxacin only to university hospitals under professional control and
after a total examination of hepatic function. In the meantime, the Commission has launched
a survey among prescribers in order to evaluate the risk/benefit balance of this product.
(Reference: (MARDMP) Letter to WHO, , , 24 Aug 1999)

ESP Jun 1999 The Spanish Medicines Agency has suspended the use of medicinal products contain the
fluoroquinolone antibiotic, trovafloxacin and the intravenous formulation of the drug,
alatrofloxacin
(Reference: (ESPAES) Communication, , , 15 June 1999)

EME May 1999 The European Agency for the Evaluation of Medicinal Products (EMEA) has recommended that marketing authorization for products containing trovafloxacin or alatrofloxacin be
suspended. This follows reports of serious adverse hepatic events.
(Reference: (EMEAPS) Public statement, No.17438/99, , May 1999)

SYR 1999 The Suprim Technical Committee and the Ministry of Health has withdrawn the licensing
approval for trovafloxacin and cancelled it from the national essential drug list.
(Reference: (SYRAFD) Announcement from the Directorate, 4/2/1989, , 02 Sep 1999)
 

On June 9, 1999, FDA issued a public health advisory to physicians concerning the risks of liver toxicity associated with the use of Trovan (trovafloxacin, an oral antibiotic) and Trovan-IV (alatrofloxacin, the intranvenous formulation of the drug). Trovan is an antibiotic used to treat many different types of infections. Trovafloxacin was approved for marketing in December, 1997, and became available on the market in February, 1998.   Based on new safety data related to serious liver injury, FDA is advising physicians that trovafloxacin should be reserved for use only in patients who meet the specific criteria outlined in the following public health advisory.

• FDA Talk Paper (6/9/1999)

• Public Health Advisory (6/9/1999)

• Trovan Questions and Answers (6/9/1999)

The Food and Drug Administration issued a public health advisory to physicians concerning the risks of liver toxicity associated with the use of Trovan (trovafloxacin, an oral antibiotic) and Trovan-IV (alatrofloxacin, the intravenous formulation of the drug). This action follows postmarketing reports of rare but severe liver injuries leading to transplants and deaths.

In issuing this advisory, FDA is informing physicians that Trovan should be reserved for use only in patients who meet all of the following criteria:

• Patients who have at least one of several specified infections such as nosocomial (hospital-acquired) pneumonia or complicated intra-abdominal infections that, in the judgment of the treating physician, is serious and life- or limb-threatening;
• Patients who begin their therapy in in-patient health care facilities (hospitals or longterm nursing care facilities);
• And patients for whom the treating physician believes that even given the new safety information, the benefit of the product outweighs the potential risks.

FDA is further informing physicians that, in general, therapy with Trovan should not continue for longer than 14 days. Therapy should be discontinued sooner if the patient experiences any clinical signs of liver dysfunction, including fatigue, loss of appetite, yellowing of the skin and eyes, severe stomach pain with nausea and vomiting, or dark urine.

FDA is also advising physicians that for most patients who meet the treatment criteria, therapy would most likely begin with intravenous Trovan. After clinical stabilization patients may be switched to the oral dosage form. Although oral therapy might be appropriate in some cases as an initial therapy, the agency emphasizes that the oral form of Trovan is not warranted for infections other than those specified.

It is estimated that 2.5 million prescriptions have been written for Trovan, a quinolone antibiotic, since its February 1998 market launch in oral and intravenous formulations. Trovan was initially approved for treating a broad range of infections, from minor skin infections to severe infections in hospitalized patients.

No reports of liver failure, liver transplant, or death due to liver problems were reported in the 7,000 patients studied in premarketing clinical trials for Trovan. In July 1998, FDA worked with the manufacturer to strengthen the product's labeling concerning liver problems after receiving reports of elevated liver enzymes and symptomatic hepatitis in patients after short- and long-term therapy. Since then, FDA has continued to receive reports of liver toxicity, including reports of a more serious nature.

FDA is now aware of 14 cases of acute liver failure that it has concluded are strongly associated with the drug. Six of these patients died: five due to liver failure and one of four additional patients who received liver transplants. Three patients recovered without requiring liver transplants, and for the remaining two patients the final outcome is still pending.

More information about Trovan, including FDA's public health advisory, is available on the World Wide Web at www.fda.gov/cder/news/trovan/default.htm and from Pfizer, the manufacturer of the drug, at 1-800-438-1985.

Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Tendon rupture can occur during or after therapy with quinolones.

Quinolones have been shown to cause arthropathy in immature animals.  Arthropathy and chondrodysplasia were observed in immature animals given trovafloxacin  Trovafloxacin has been shown to cause arthropathy in immature rats and dogs. In addition, these drugs are associated with an increased incidence of chondrodysplasia in rats compared to controls. As with other members of the quinolone class, trovafloxacin has caused arthropathy and/or chondrodysplasia in immature rats and dogs.Quinolones, including trovafloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species .

Quinolones have been reported to have proconvulsant activity that is exacerbated with concomitant use of non-steroidal antiinflammatory drugs (NSAIDS).

Convulsions, increased intracranial pressure and psychosis have been reported in patients receiving quinolones. Quinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, and insomnia. These reactions may occur following the first dose.

As with other members of the quinolone class, trovafloxacin produces testicular degeneration in rats and dogs dosed for 6 months.

During the post-marketing period, TROVAN-associated liver enzyme abnormalities and/or symptomatic hepatitis have occurred during short-term or long-term therapy

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones. These reactions may occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions.

Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving therapy with all antimicrobials. 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.

Moderate to severe phototoxicity reactions have been observed in patients who are exposed to direct sunlight while receiving some drugs in the quinolone class. Therapy should be discontinued if phototoxicity (e.g., a skin eruption, etc.) occurs.

During the post-marketing period, TROVAN-associated liver enzyme abnormalities and/or symptomatic hepatitis have occurred during short-term or long-term therapy. Liver enzyme abnormalities have been reported in both men and women. Liver failure (including acute hepatic necrosis with eosinophilic infiltration) has also been reported rarely. Symptomatic pancreatitis has been reported on therapy. Clinicians should monitor liver function tests and pancreatic tests in patients who develop symptoms consistent with hepatitis and/or pancreatitis as clinically indicated.

Trovafloxacin is excreted in human milk and was found in measurable concentrations in the milk of lactating subjects 

Administration of trovafloxacin (200 mg) concomitantly with caffeine (200 mg) resulted in a 17% increase in caffeine AUC and a 15% increase in caffeine Cmax.

ADVERSE REACTIONS

Quinolones have been shown to cause arthropathy in immature animals.

Arthropathy and chondrodysplasia were observed in immature animals given trovafloxacin

Trovafloxacin has been shown to cause arthropathy in immature rats and dogs. In addition, these drugs are associated with an increased incidence of chondrodysplasia in rats compared to controls.

Unlike some other members of the quinolone class, crystalluria and ocular toxicity were not observed in chronic safety studies with rats or dogs with either trovafloxacin or its prodrug, alatrofloxacin.

Quinolones have been reported to have proconvulsant activity that is exacerbated with concomitant use of non-steroidal antiinflammatory drugs (NSAIDS).

As with other members of the quinolone class, trovafloxacin produces testicular degeneration in rats and dogs dosed for 6 months.

At a dose of trovafloxacin 10 times the highest human dose based on mg/kg or approximately 5 times based on mg/m², elevated liver enzyme levels which correlated with centrilobar hepatocellular vacuolar degeneration and necrosis were observed in dogs in a 6-month study. A subsequent study demonstrated reversibility of these effects when trovafloxacin was discontinued.

TROVAN was discontinued for adverse events thought related to drug in 5% of patients

Dizziness, nausea, headache, and vomiting ients.

Application Injection Insertion Site: Application/injection/insertion site device complications, inflammation, pain, edema

Autonomic Nervous: flushing, increased sweating, dry mouth, cold clammy skin, increased saliva

Cardiovascular: peripheral edema, chest pain, thrombophlebitis, hypotension, palpitation, periorbital edema, hypertension, syncope, tachycardia, angina pectoris, bradycardia, peripheral ischemia, edema, dizziness postural

Central Peripheral Nervous System: confusion, paresthesia, vertigo, hypoesthesia, ataxia, convulsions, dysphonia, hypertonia, migraine, involuntary muscle contractions, speech disorder, encephalopathy, abnormal gait, hyperkinesia, hypokinesia, tongue paralysis, abnormal coordination, tremor, dyskinesia

Gastrointestinal: altered bowel habit, constipation, Clostridium difficile-associated diarrhea, dyspepsia, flatulence, loose stools, gastritis, dysphagia, increased appetite, gastroenteritis, rectal disorder, colitis, pseudomembranous colitis, enteritis, eructation, gastrointestinal disorder, melena, hiccup

Oral Cavity: gingivitis, stomatitis, altered saliva, tongue disorder, tongue edema, tooth disorder, chelitis, halitosis

General Other: fever, fatigue, pain, asthenia, moniliasis, hot flushes, back pain, chills, infection (bacterial, fungal), malaise, sepsis, alcohol intolerance, allergic reaction, anaphylactoid reaction, drug (other) toxicity/reaction, weight increase, weight decrease

Hematopoietic: anemia, granulocytopenia, hemorrhage unspecified, leukopenia, prothrombin decreased, thrombocythemia, thrombocytopenia

Liver Biliary: increased hepatic enzymes, hepatic function abnormal, bilirubinemia, discolored feces, jaundice

Metabolic Nutritional: hyperglycemia, thirst

Musculoskeletal: arthralgia, muscle cramps, myalgia, muscle weakness, skeletal pain, tendinitis, arthropathy

Psychiatric: anxiety, anorexia, agitation, nervousness, somnolence, insomnia, depression, amnesia, concentration impaired, depersonalization, dreaming abnormal, emotional lability, euphoria, hallucination, impotence, libido decreased-male, paroniria, thinking abnormal

Reproductive: Female: leukorrhea, menstrual disorder; Male: balanoposthitis

Respiratory: dyspnea, rhinitis, sinusitis, bronchospasm, coughing, epistaxis, respiratory insufficiency, upper respiratory tract infection, respiratory disorder, asthma, hemoptysis, hypoxia, stridor

Skin/Appendages: pruritus ani, skin disorder, skin ulceration, angioedema, dermatitis, dermatitis fungal, photosensitivity skin reaction, seborrhea, skin exfoliation, urticaria

Special Senses: taste perversion, eye pain, abnormal vision, conjunctivitis, photophobia, conjuctival hemorrhage, hyperacusis, scotoma, tinnitus, visual field defect, diplopia, xerophthalmia

Urinary System: dysuria, face edema, micturition frequency, interstitial nephritis, renal failure acute, renal function abnormal, urinary incontinence

Laboratory Changes Trovafloxacin

Changes in laboratory parameters were:
 decreased hemoglobin and hematocrit; increased platelets; decreased and increased WBC; eosinophilia; increased ALT (SGPT), AST (SGOT), and alkaline phosphatase; decreased protein and albumin; increased BUN and creatinine; decreased sodium; and bicarbonate.

Adverse reactions reported with TROVAN during the post-marketing period include:
anaphylaxis, symptomatic hepatitis (some patients experienced an associated peripheral eosinophilia), liver failure (including acute hepatic necrosis with eosinophilic infiltration), Stevens-Johnson Syndrome, and symptomatic pancreatitis.

During the post-marketing period, TROVAN-associated liver enzyme abnormalities and/or symptomatic hepatitis have occurred during short-term or long-term therapy

Administration of trovafloxacin (200 mg) concomitantly with caffeine (200 mg) resulted in a 17% increase in caffeine AUC and a 15% increase in caffeine Cmax.

As with other members of the quinolone class, trovafloxacin has caused arthropathy and/or chondrodysplasia in immature rats and dogs.

Convulsions, increased intracranial pressure and psychosis have been reported in patients receiving quinolones. Quinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, lightheadedness, confusion, hallucinations, paranoia, depression, nightmares, and insomnia. These reactions may occur following the first dose.

As with other quinolones, TROVAN should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral atherosclerosis, epilepsy, and other factors that predispose to seizures

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving therapy with quinolones. These reactions may occur following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension/shock seizure, loss of consciousness, tingling, angioedema (including tongue, laryngeal, throat or facial edema/swelling), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, itching, and other serious skin reactions.

TROVAN should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require treatment with epinephrine and other resuscitative measures, including oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated

Serious and sometimes fatal events, some due to hypersensitivity and some due to uncertain etiology, have been reported in patients receiving therapy with all antimicrobials. 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.

Ruptures of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. TROVAN should be discontinued if the patient experiences pain, inflammation or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded. Tendon rupture can occur during or after therapy with quinolones.

Moderate to severe phototoxicity reactions have been observed in patients who are exposed to direct sunlight while receiving some drugs in the quinolone class. Therapy should be discontinued if phototoxicity (e.g., a skin eruption, etc.) occurs.

During the post-marketing period, TROVAN-associated liver enzyme abnormalities and/or symptomatic hepatitis have occurred during short-term or long-term therapy. Liver enzyme abnormalities have been reported in both men and women. Liver failure (including acute hepatic necrosis with eosinophilic infiltration) has also been reported rarely. Symptomatic pancreatitis has been reported on therapy. Clinicians should monitor liver function tests and pancreatic tests in patients who develop symptoms consistent with hepatitis and/or pancreatitis as clinically indicated.

An increase in skeletal variations and malformations was observed in rat fetuses after daily intravenous doses of alatrofloxacin at >/=20 mg/kg/day (approximately 4 times the highest recommended human dose based on mg/kg or 0.6 times based upon body surface area) were administered to dams during organogenesis. In the rabbit, an increase in fetal skeletal malformations was also observed when 20 mg/kg/day (approximately equal to the highest recommended human dose based upon body surface area) of alatrofloxacin was given intravenously during the period of organogenesis. Intravenous dosing of alatrofloxacin at 6.5 mg/kg in the rat or rabbit was not associated with an increased incidence of skeletal variations or malformations. Fetotoxicity and fetal skeletal malformations have been associated with other quinolones.

Oral doses of trovafloxacin >5 mg/kg were associated with an increased gestation time in rats, and several dams at 75 mg/kg experienced uterine dystocia.

Trovafloxacin is excreted in human milk and was found in measurable concentrations in the milk of lactating subjects 

Because of the potential for unknown effects from trovafloxacin in nursing infants from mothers taking trovafloxacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Quinolones, including trovafloxacin, cause arthropathy and osteochondrosis in juvenile animals of several species .