The Fluoroquinolone Toxicity Research Foundation

 
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The recent changes (July 2004) regarding the warnings included in the following fluoroquinolone package inserts indicate that:

Peripheral Neuropathy
Pseudomembranous Colitis
Spontaneous Tendon Rupture

are all CLASS EFFECTS regarding this class of chemotherapeutic agents.  Yet we do not find ANY SUCH WARNINGS regarding these adverse reactions within the inserts for Factive.  Nor do we find anything suggesting that this is an IRREVERSIBLE CONDITION within the inserts for Avelox or Factive, as we find for 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.")

We also do not find any reference to treating Pseudomembranous Colitis within the Factive package insert as we find for Cipro.  We find only a vague reference to this once again being a class effect:

"Antibiotic Associated Colitis: Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Gemifloxacin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of any antibacterial agent."

The only change we find regarding Factive is a generic warning regarding scripting abuse contributing to drug resistance:

"SYSTEMIC ANTIBACTERIAL DRUG PRODUCTS STATEMENT to reduce the development of drug-resistant bacteria."

Noroxin is also missing the statements regarding the treatment protocol for Pseudomembranous Colitis.  Avelox, as well as Noroxin, is also missing the warning that tendon rupture can occur during or after therapy with quinolones. Avelox. Cipro IV and Cipro Tab  are also missing the warnings that the risk of such ruptures may be increased in patients receiving concomitant corticosteroids, especially the elderly. Yet for some reason we do find this warning included in Cipro XR.  The lack of consistency regarding these warnings is baffling to me.

The following are the changes have been made to Avelox, Factive, Cipro and Noroxin that I am referring to:

Changes made to the package insert for Avelox:

WARNINGS
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. {notice the lack of warning regarding the fact that this is irreversible}

Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including Moxifloxacin. {notice the lack of warning regarding the use of steroids as well as the warnings regarding the fact that tendon rupture can occur during or after therapy with quinolones}

Changes made to the package insert for Cipro IV:
WARNINGS
Pseudomembranous Colitis: After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit peristalsis should be avoided.

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.

Tendon Effects: Ciprofloxacin 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 excluded. Tendon rupture can occur during or after therapy with quinolones, including Ciprofloxacin. {notice the lack of warning regarding the use of steroids}

Changes made to the package insert for Cipro Tab:

WARNINGS
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

Tendon Effects: Ciprofloxacin 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 excluded. Tendon rupture can occur during or after therapy with quinolones, including Ciprofloxacin. {notice the lack of warning regarding the use of steroids}


Changes made to the package insert for Cipro XR:

WARNINGS
Pseudomembranous Colitis: After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit peristalsis should be avoided.

Peripheral Neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy 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.

Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including Ciprofloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Ciprofloxacin 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 excluded. Tendon rupture can occur during or after therapy with quinolones, including Ciprofloxacin.

Changes made to the package insert for Noroxin:

WARNINGS
Peripheral Neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or largeaxons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including Norfloxacin. Norfloxacin 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.

Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including Norfloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly. {notice the lack of warning regarding the fact that tendon rupture can occur during or after therapy with quinolones}


Logic would dictate that if indeed these adverse reactions are a class effect then such warnings should be added to all drugs within this class, yet once again we find a "hit and miss" approach being utilized by the FDA.  What is even more disturbing is the fact that Levaquin, which has the highest CNS and PNS adverse drug reaction profile associated with it, does not appear to contain the warning referred to above regarding Peripheral Neuropathy, the use of steroids and the treatment protocol for Pseudomembranous Colitis. Nor do we appear to find such warnings for Tequin, Floxin and other such drugs within this class.

Considering the fact that Ciprofloxacin will be replaced by generic equivalents, if it has not been already, once has to question why the warnings that clearly indicate that Peripheral Neuropathy is IRREVERSIBLE is glaringly absent from Bayer's replacement, Avelox, but is quite prominent in Noroxin which is a competing drug within the same class.

The failure to include the class effect warnings in ALL of the package inserts for ALL of the drugs within this class has resulted in the drugs that fail to contain such warnings should now to be considered misbranded.  Therefore logic  would dictate that the FDA be required to take the necessary action to correct this situation by adding the following warnings, prominently displayed, within the package inserts for all chemotherapeutic drugs within this class:

WARNINGS
Pseudomembranous Colitis: After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit peristalsis should be avoided.

Peripheral Neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones.  Therapy 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.

Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Therapy 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 excluded. Tendon rupture can occur during or after therapy with quinolones.