From the AJC:
The business climate in Georgia is surpassed only by Texas and North Carolina, according to a study by marketing company Development Counsellors International.
Georgia was followed by Tennessee and Florida, which tied for fourth place. Some 20.4 percent said Georgia was the state with the most favorable climate. Executives usually cited three factors for their choices: a strong labor market, low operating costs and a pro-business climate.
“With the battle for business more intense than ever, states and their economic development organizations need to pay close attention to the results of this survey,” DCI President Andrew T. Levine said in a statement. “Whether accurate or misguided, perceptions about a location’s business climate often play a crucial role in site selection decisions and where companies invest money and create jobs.”
DCI said its survey was sent to a random selection of 3,591 U.S. companies with annual revenue of at least $25 million.
My comment: This is so even though each year state partisan politics trots out the need for reform in the justice system.
Tuesday, July 29, 2008
FDA Execs Received "Lavish" Bonuses
As if the FDA's weekly bludgeoning at the hands of Congress is not enough, there is this news:
Congressman Bart Stupak informs that 28 senior FDA executives took in a combined $1 million in bonuses last year. To me, this news is obscene. Clearly the FDA is a weak guardian when it comes to the safety of drugs and food. Yet, with this news, you would think that perhaps the entire system has gone mad.
Bonuses for FDA bureaucrats? Yep. Look at these examples:
$48,000 in a cash award and retention bonus went to an associate commissioner whose plan to overhaul FDA field labs was rejected by Congress as poorly thought-out.
$41,000 went to the director of the office of criminal investigations, pushing his total income to enforce one statute to $208,000 - more than the director of the FBI makes.
What's most galling? CBS News notes that "The person who was hired to reform the bonus system received the biggest bonus, $58,000."
Nearly 25% of the $35 million in bonuses the FDA handed out last year went to bureaucrats, not technical experts.
For more go here.
Congressman Bart Stupak informs that 28 senior FDA executives took in a combined $1 million in bonuses last year. To me, this news is obscene. Clearly the FDA is a weak guardian when it comes to the safety of drugs and food. Yet, with this news, you would think that perhaps the entire system has gone mad.
Bonuses for FDA bureaucrats? Yep. Look at these examples:
$48,000 in a cash award and retention bonus went to an associate commissioner whose plan to overhaul FDA field labs was rejected by Congress as poorly thought-out.
$41,000 went to the director of the office of criminal investigations, pushing his total income to enforce one statute to $208,000 - more than the director of the FBI makes.
What's most galling? CBS News notes that "The person who was hired to reform the bonus system received the biggest bonus, $58,000."
Nearly 25% of the $35 million in bonuses the FDA handed out last year went to bureaucrats, not technical experts.
For more go here.
Monday, July 28, 2008
Selenium: Link to Diabetes?
From various sites:
A new analysis of data from a large national study found that people who took a 200 microgram selenium supplement each day for almost eight years had an increased risk of developing type 2 diabetes than those who took a placebo or dummy pill.
The data came from the Nutritional Prevention of Cancer Trial (NPC), a large randomized, multi-center, clinical trial. It was designed to evaluate whether selenium supplements prevent skin cancer. In the study being published, researchers selected 1,202 participants who did not have diabetes when they were enrolled in the NPC Trial. Half received a 200 microgram selenium supplement and half received a placebo pill for an average of 7.7 years.
Link to at least one site here.
A new analysis of data from a large national study found that people who took a 200 microgram selenium supplement each day for almost eight years had an increased risk of developing type 2 diabetes than those who took a placebo or dummy pill.
The data came from the Nutritional Prevention of Cancer Trial (NPC), a large randomized, multi-center, clinical trial. It was designed to evaluate whether selenium supplements prevent skin cancer. In the study being published, researchers selected 1,202 participants who did not have diabetes when they were enrolled in the NPC Trial. Half received a 200 microgram selenium supplement and half received a placebo pill for an average of 7.7 years.
Link to at least one site here.
Digitek Recall
My good friend Angel Reyes and his firm are based in Dallas, Texas and his firm has a national reputation. From their site:
"Heygood, Orr, Reyes, Pearson & Bartolomei is a business litigation and personal injury law firm, based in Dallas, Texas. We have worked with executives, business owners, and individuals to try over 300 cases to a jury verdict."
The firm is a drug known as Digitek.
Eric Pearson's report - it's copyrighted:
Digitek is the trade name for digoxin tablets manufactured in the United States by Actavis Totowa, LLC, the U.S. manufacturing division of international generic pharmaceutical company Actavis Group. The tablets are distributed in the U.S. by Mylan Pharmaceuticals, based in Morgantown, West Virginia and by UDL Laboratories, based in Rockford, Illinois. Both Mylan Pharmaceuticals and UDL are owned by parent company Mylan, a drug company based in Pittsburgh, Pennsylvania with a market cap of $4 billion. The tablets are distributed by Mylan under a “Bertek” label and by UDL under a “UDL” label. It appears that the tablets distributed under the UDL label are distributed to hospitals and other health care facilities in unit dose form in a foil blister pack. The tablets distributed by Mylan under the Bertek label are believed to have been distributed in standard pill bottles.
The Digitek tablets are manufactured by Actavis Totowa in their Elizabeth, New Jersey plant. Their website describes the plant as a “solid-oral-does facility for tablets and capsules supporting a broad therapeutic range” with a “core competency on modified-release products.” The FDA has a different take on the competency of this facility. As set forth in the Warning Letter attached hereto as Exhibit A, the FDA conducted a plant inspection from January 10 through February 6, 2006 and found numerous issues of concern, including:
● Failure to submit required FDA Adverse Drug Experience (“ADE”) Reports;
● Failure to promptly investigate serious and unexpected ADE reports;
● Failure to ever file a required Periodic Safety Report;
● Manufacturing numerous prescription drug products without approved applications.
Digitek was approved by the FDA through a process known as an Abbreviated New Drug Application (“ANDA”). An ANDA applies to a generic equivalent of a prescription drug that has already received FDA approval. The already-approved drug on which Actavis based its ANDA was Lanoxin, a digoxin tablet manufactured by GlaxoSmithKline. In order to secure FDA approval, Actavis was required to demonstrate that its Digitek tablets were “bioequivalent” in comparison to Lanoxin. Bioequivalence factors scrutinized by the relevant authorities concern active ingredient(s), quality, safety, dosage forms and strengths, performance characteristics and intended use. Actavis’ ANDA No. 40-282 was approved by the FDA by letter dated December 23, 1999.
III. The Digitek recall.
On April 25, 2008, Actavis announced a recall of all lots of Bertek and UDL Laboratories Digitek tablets. According to its Press Release, attached hereto as Exhibit B, Actavis initiated the voluntary all-lot recall because “due to the possibility that tablets with double the appropriate thickness may have been commercially released.” Actavis further stated that “[t]hese tablets may contain twice the approved level of active ingredient than is appropriate.” Further, according to the Actavis Press Release:
The existence of double strength tablets poses a risk of digitalis toxicity in patients with renal failure. Digitalis toxicity can cause nausea, vomiting, dizziness, low blood pressure, cardiac instability and bradycardia. Death can also result from excessive Digitalis intake. Several reports of illnesses and injuries have been received.
IV. Dosing issues.
Digitek tablets are sold in two doses, .125 mg and .25 mg. A study of patients given a single .25 mg daily dose of digoxin showed a median digoxin concentration level of .9 ng/mL for women and .8 ng/mL for men. Rathore, Sex-Based differences in the Effect of Digoxin for the Treatment of Heart Failure. Long-term results from the same study showed a mean digoxin concentration of .97 to 1.01 ng/mL between all sexes. Id. Similar data was obtained from a large scale study completed in 1997. Among 1485 patients, the mean digoxin level for patients taking a .25 mg tablet was .89 ng/mL.”). The Digitalis Investigation Group, The Effect of Digoxin on Mortality and Morbidity in Patients With Heart Failure. That same study showed a mean digoxin level for patients taking a .125 mg tablet of .76 ng/mL. Id.
According to data provided to the FDA in Actavis’ NDA, a patient given two of the .25 mg tablets will typically have an immediate mean serum concentration level of between 1.8 ng/mL and 2.0 ng/mL. The concentration level is expected to rapidly decline to a level of less than .6 ng/mL within six to eight hours.
According to information provided to the FDA by the makers of Lanoxin, about two-thirds of adult patients considered adequately dosed with digoxin (and without evidence of toxicity) have serum digoxin concentrations ranging from .8 to 2.0 ng/mL. About two-thirds of patients suffering from digitalis toxicity have serum digoxin concentrations above 2.0 ng/mL while one-third have levels below 2.0 ng/mL.
According to Baselt, Disposition of Toxic Drugs and Chemicals in Man, Seventh Edition, peak serum concentrations of digoxin measured in a variety of clinical tests ranged from 1.13 ng/mL to 2.4ng/mL depending on dosage. Baselt also states that one study of 48 patients exhibiting signs of digoxin toxicity found average serum concentrations of digoxin of 3.7 ng/mL with a range from 1.6 ng/mL to 13.7 ng/mL. another study of some 1000 patients found a mean serum digoxin level in nontoxic patients of 1.4 ng/mL. Bhatia, Digitalis Toxicity—Turning Over a New Leaf. Although the serum digoxin level in patients with toxicity was two to three times higher, “there was considerable overlap between the two groups of patients.” Id.
The foregoing data demonstrates that digoxin has a very narrow therapeutic range. As one medical publication has explained:
Digoxin has a narrow therapeutic window: that is to say, there is only a small range of plasma concentration between the drug being ineffective through underdosing, and toxic through overdosing.
This conclusion has been borne out by a variety of studies found in the medical literature. See, e.g., THCP Education Consortium, Digoxin Toxicity (“There is a narrow therapeutic range for digoxin – which means that the patient can easily have too much or too little of the drug on board.”). Based on the available literature, it appears clear that a double dose of digoxin could lead to digoxin toxicity.
V. Possible side effects of digoxin use.
According to the Lanoxin Product Insert (which is identical to the Digitek product insert), attached hereto as Exhibit C, various side effects may arise from the use of digoxin. Adverse reactions are generally dose-dependent. Exhibit C at p. 7. In the past, approximately one-half of all adverse reactions were cardiac in nature. Id. One-fourth of all adverse reactions were gastrointestinal and the final one-fourth were related to the central nervous system (“CNS”).
A.Cardiac events.
As stated above, about one-half of previously reported adverse events were cardiac in nature. According to the product insert, among the cardiac problems that may be caused from a high dose of digoxin are the following:
first-degree, second-degree (Wenckebach) or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation.
Exhibit C at p. 7. Baselt, Disposition of Toxic Drugs and Chemicals in Man, Seventh Edition, lists possible cardiac side effects as “cardiac disturbances such as tachycardia, premature contractions, atrial fibrillation and atrioventricular block.” Manifestations of these cardiac events include palpitations, loss of consciousness and difficulty breathing.
B.Gastrointestinal events.
Gastrointestinal events caused by digoxin may include anorexia, nausea, vomiting and diarrhea. Other, less frequent, events include abdominal pain, intestinal ischemia and hemorrhagic necrosis of the intestines.
C.Central nervous system and other adverse events.
Events related to the central nervous system include visual disturbances such as blurred or yellow vision, headaches, weakness, dizziness, apathy and confusion. Other possible side effects include mental disturbances such as anxiety, depression, delirium and hallucinations. Gynecomastia, or breast enlargement in males, has also been reported.
VI. Digoxin toxicity.
A.General principles.
Digitek tablets are sold in two doses, .125 mg and .25 mg. A patient given two of the .25 mg tablets will typically have an immediate mean serum concentration level of between 1.8 ng/mL and 2.0 ng/mL. According to information provided to the FDA by the makers of Lanoxin, about two-thirds of adult patients considered adequately dosed with digoxin (and without evidence of toxicity) have serum digoxin concentrations ranging from .8 to 2.0 ng/mL. According to Baselt, Disposition of Toxic Drugs and Chemicals in Man, Seventh Edition, peak serum concentrations of digoxin measured in a variety of clinical tests ranged from 1.13 ng/mL to 2.4ng/mL depending on dosage.
While the highest strength Digitek tablet is .25 mg, Lanoxin used to be prescribed in doses up to .5 mg. In fact, when Actavis did testing of their .25 mg pill, they gave the subjects two of the pills (or .5 mg) because they were attempting to replicate studies that GlaxoSmithKline had done on their .5 mg pills. Thus, a patient taking one .25 mg Digitek tablet that contained a double dose of digoxin would arguably be expected to achieve the same digoxin serum level as did those patients in the clinical trials conducted by Actavis: a mean serum concentration level of between 1.8 ng/mL and 2.0 ng/mL.
Unfortunately, there are many problems with drawing a bright-line rule from the available data and studies. First, the effects of digoxin are highly variable among patients. Second, the narrow therapeutic range of digoxin makes it difficult to determine whether a particular digoxin level is therapeutic or toxic in a particular patient:
Considering there is some overlap between therapeutic and toxic serum digoxin levels, symptoms of toxicity may be reported in patients whose levels are within the therapeutic range, while others may have no symptoms hen their serum digoxin levels are above the therapeutic threshold.
Hixson-Wallace, Digoxin Toxicity: A Review. Finally, digoxin levels taken less than 6 hours after the administration of digoxin may overstate the true digoxin level. See Williamson, Digoxin Toxicity: An Evaluation in Current Clinical Practice. As stated in the Lanoxin Product Insert:
Following drug administration, a 6- to 8-hour distribution phase is observed. . . . clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action . . . . To allow adequate time for equilibration of digoxin between serum and tissue, sampling of serum concentrations should be done just before the next scheduled dose of the drug. If this is not possible, sampling should be done at least 6 to 8 hours after the last dose, regardless of the route of administration or the formula used.
Exhibit C at pp. 3, 9. When reviewing any digoxin serum concentration level, it is important to know when it was drawn relative to the ingestion of digoxin.
B.Digoxin levels as a predictor of digoxin toxicity.
Despite the foregoing issues, properly obtained digoxin levels remain the best indicator of digoxin toxicity. A digoxin level of 3.0 ng/mL or greater is a strong predictor of digoxin toxicity:
Baselt states that one study of 48 patients exhibiting signs of digoxin toxicity found average serum concentrations of digoxin of 3.7 ng/mL.
Another study of some 1000 patients found a mean serum digoxin level in patients suffering from digoxin toxicity of 2.8 ng/mL to 4.2 ng/mL. Bhatia, Digitalis Toxicity—Turning Over a New Leaf.
A study of nearly 800 patients in Japan found that all patients with a digoxin level over 3.0 ng/mL exhibited clinical evidence of digoxin toxicity.” Miura, Effect of Aging on the Incidence of Digoxin Toxicity.
One study showed that “the risk of toxicity at a digoxin concentration of higher than 3.0 ng/mL was 12-fold the risk of at a serum concentration of 0 to .99 ng/mL.” Bhatia, Digitalis Toxicity—Turning Over a New Leaf.
A study of more than 2000 patients found that the mean digoxin serum concentration level for patients with definite digoxin toxicity was 3.6 ng/mL and the mean level for patients with possible digoxin toxicity was 3.4 ng/mL. Williamson, Digoxin Toxicity: An Evaluation in Current Clinical Practice.
One author has concluded that “although no serum digoxin level proves or disproves toxicity, a level higher than 3.0 ng/mL in the appropriate setting lend strong support to diagnosis of digitalis excess.” Bhatia, Digitalis Toxicity—Turning Over a New Leaf.
A digoxin level greater than 2.0 ng/mL is also a fair predictor of digoxin intoxication. A study from North Carolina showed that 60% of patients with a digoxin level over 2.0 ng/mL that was measured more than 6 hours after administration of digoxin had clinical evidence of digoxin toxicity. Williamson, Digoxin Toxicity: An Evaluation in Current Clinical Practice.
A digoxin level below 2.0 ng/mL is a possible indicator of digoxin toxicity. Anywhere from 10% to 33% of patients with such a level may experience adverse side effects as a result of digoxin toxicity:
One study of some 1000 patients showed that 10% of patents with digoxin toxicity had serum concentrations of less than 2.0 ng/mL. Smith, Digitalis Glycosides: Mechanism and Manifestation of Toxicity.
As stated in the Lanoxin Product Insert: “since one-third of patients with clinical toxicity have serum digoxin concentrations less than 2.0 ng/mL, values below 2.0 ng/mL do not rule out the possibility that a certain sign or symptom is related to digoxin therapy.”
A study in Japan “showed that there was an overlapping (toxic and nontoxic) range of serum digoxin concentrations in which the incidence of digoxin toxicity was patient dependent (1.4 – 2/9 ng/mL).” Miura, Effect of Aging on the Incidence of Digoxin Toxicity.
Baselt states that one study of 48 patients exhibiting signs of digoxin toxicity found average digoxin serum concentrations ranging from 1.6 to 13.7 ng/mL.
Another study of some 1000 patients found “considerable overlap” in the digoxin serum concentration levels of nontoxic and toxic patients. Bhatia, Digitalis Toxicity—Turning Over a New Leaf.
Clearly, there will be many patients --- perhaps between 10 and 33% -- with a digoxin level below 2.0 ng/mL who will suffer the effects of digoxin toxicity.
C.At-risk patients.
Of course, certain patients are more susceptible to digoxin toxicity, and the above conclusions do not apply to those patients. This includes elderly patients. See Schreiber, Digitalis Toxicity (“Advanced age (>80) is an independent risk factor and is associated with increased morbidity and mortality.”); Miura, Effect of Aging on the Incidence of Digoxin Toxicity (“clinical evidence of digoxin toxicity in patients > 71 years old was 26.5%, despite their SDCs falling between 1.4 and 2.0 ng/mL . . . . “[t]his raises the possibility that patients > 71 years show clinical evidence of digoxin toxicity despite having SDCs within the recommended therapeutic range.”).
Patients who have previously suffered from renal failure are also particularly susceptible to digoxin toxicity. Exhibit C at p. 5 (“[i]f appropriate care is not taken to reduce the dose of digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function.”). Other at-risk patients are those with electrolyte disorders such as hypokalemia (low blood potassium), hypomagnesemia (magnesium deficiency) or hypocalcemia (low blood calcium levels). Exhibit C at p. 5. Patients with thyroid disorders are also especially at risk. Exhibit C at p. 5.
D.Symptoms of digoxin toxicity.
Although increased digoxin levels may be a good predictor of digoxin toxicity, the ultimate issue from a damage perspective is whether a patient suffered any injury because of digoxin toxicity. As one author has noted, “clinically stable patients receiving digoxin who have elevated SDCs but are without signs or symptoms of digoxin toxicity are at low risk of developing serious digoxin toxicity and do not generally require treatment beyond the discontinuation of digoxin therapy.” Park, Digoxin Toxicity in Patients with High Serum Digoxin Concentrations. Thus, it is important to be aware of the most prevalent symptoms of digoxin toxicity.
1.Cardiac events.
Increased congestive heart failure may be the initial manifestation of digitalis toxicity in as many as 7.5% of patients. Dysrhythmia, or an abnormal heart rate, occurs in 80% to 90% of patients with digitalis toxicity. Bhatia, Digitalis Toxicity—Turning Over a New Leaf. Perhaps the earliest cardiac manifestation of digoxin toxicity in many patients is premature ventricular contraction (”PVC”). The Digitalis Investigation Group, The Effect of Digoxin on Mortality and Morbidity in Patients With Heart Failure. Ventricular fibrillation and tachycardia are also common symptoms.
The type of arrhythmia will often indicate whether a cardiac event has been caused by digitalis toxicity. Among the types of arrhythmias most suggestive of digitalis toxicity are the following:
● Bidirectional ventricular tachycardia
● Bigeminal ventricular Rhythm
● Multiform premature ventricular complexes
● Atrial tachycardia with block
● Nonparoxysmal AV junctional tachycardia
● Supraventricular rhythm (atrial fibrillation) with ventricular ectopy
● Nonconducted premature atrial complexes
● Ventricular tachycardia with exit block
Bhatia, Digitalis Toxicity—Turning Over a New Leaf. HJJ Wellens has developed four criteria for the electrocardiographic diagnosis of digitalis toxicity. They are:
1.Appearance of a slow heart rate in a patent with a fast or normal heart rate;
2.Appearance of a fast heart rate in a patient with a normal heart rate;
3.Appearance of a regular heart rhythm in a patient with an irregular rhythm; and
4.Appearance of a regularly irregular rhythm.
Wellens, HHJ, The Electrocardiogram in Digitalis Intoxication. Other authors suggest that the most common EKG changes in digoxin toxicity are PR-segment prolongation and cupping of the ST segment. Another author has stated that the typical “digitalis effect” found in electrocardiogram readings are manifested by a shortened QT interval and a characteristic down-sloping ST depression with the T wave opposite in polarity to the QRS complex. TCHP Education Consortium, Digoxin Toxicity.
2.Other events.
The first symptoms of digitalis are often gastrointestinal – anorexia, nausea, vomiting, and diarrhea. THCP Edcuation Consortium, Digoxin Toxicity. The most common symptom associated with digoxin toxicity is nausea. Williamson, Digoxin Toxicity: An Evaluation in Current Clinical Practice. Other, non-cardiac events associated with digoxin toxicity include:
● fatigue
● dizziness
● confusion
● delirium
● blurred vision
● disturbed color perception
● hallucinations
● abdominal pain
● headaches
The most common vital sign abnormality is bradycardia.
3.Death.
According to the Lanoxin Product Insert, “manifestations of life-threatening toxicity include ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhymthias, or heart block.” Exhibit C at p. 8. The Product Insert also states that “the administration of more than 10 mg of dioxin in a previously healthy adult . . . often results in cardiac arrest.” Id. Of course, this information is of limited utility because most patients taking dioxin tablets already suffer from some type of heart problem and cannot be considered “healthy adults.” As a result, they are more susceptible to cardiac arrest. This fact also complicates the diagnosis of cardiac events attributable to digitalis toxicity.
A 2005 study by K.F. Adams and others “demonstrated a significant linear relationship between serum digoxin concentration and mortality.” Adams, Relationship of Serum Digoxin Concentration to Mortality. According to a 1997 study by the American Association of Poison Control Centers, of the patients who reported digitalis toxicity, approximately 1% died. Another study showed that 3 of 20 (15%) of patients diagnosed with digoxin toxicity died despite appropriate intervention. Williamson, Digoxin Toxicity: An Evaluation in Current Clinical Practice. The Emergency Response Card for Digoxin published by the National Institute for Occupational Safety and Health states that severe exposures to digoxin may result in death, Perhaps most importantly, in its Recall Notice submitted to the FDA, Actavis stated that “[d]eath can result from excessive digitalis intake.” Exhibit B. Clearly, digitalis toxicity can lead to death.
Some of the predictors of whether digoxin toxicity can cause death are the serum digoxin concentration and the age of the patient. My compilation and analysis of data from the last five years of the Annual Report of the American Association of Poison Control Centers’ National Poison Data System yielded valuable insight into these predictors. According to the data, the mean serum digoxin level of patients who died from digoxin toxicity was 4.27 ng/mL. Further, 75% of fatalities from digoxin toxicity occurred with digoxin levels of 3.0 ng/mL or greater. With respect to age, the mean age of a patient judged to have died from digoxin toxicity was 78.5 years. Nearly 80% of all digoxin toxicity fatalities occurred in patients aged 70 years or older. None occurred in patients under the age of 60.
Finally, it is stating the obvious to note that the more pills a patient is taking, the greater the likelihood that a double-dose pill would cause death due to digoxin toxicity. Digitek is manufactured in .125 and .25 mg tablets. A typical daily therapeutic dose is .25 mg. However, patients are sometimes instructed to take several tablets per day in order to reach the desired digoxin level. As set forth in the Lanoxin Product Insert, “if rapid digitialization is considered medically appropriate, it may be achieved by administering a loading dose based upon projected peak digoxin body stores.” Exhibit C at p. 10 (“digitalization” simply refers to the use of digitalis glycosides such as dioxin to treat heart failure). Although the Lanoxin Product Insert provides information regarding an appropriate “loading dose,” it does so only with respect to digoxin injections. Medical literature, however, suggests that an appropriate loading does for digoxin tablets would an initial dose of .5 mg followed by additional doses of .25 mg to .5 mg every 6 hours until digitalization is achieved. Arnsdorf, Method of Digitalization. The total oral dose needed for digitalization is typically 1 to 2 mg using oral digoxin tablets.
Thus, in patients where rapid digitalization has been ordered, the patient may take up to 2 mg of digoxin tablets in one 24-hour period. Patients taking multiple doses of Digitek during a 24-hour period are much more likely to suffer a fatal digoxin overdose from a double-strength pill than those taking one .125 or .25 mg pill per day. We should therefore be on the lookout for injuries and deaths suffered by patients undergoing an initial “loading dose” of Digitek.
VII. What to look for in a case.
Given all of the above, what questions should an attorney ask when assessing potential cases against Actavis as a result of a double-dose of Digitek?
● Does the patient have the pills?
● What strength pills were prescribed?
● How frequently were they taking the pills?
● Was the patient in the middle of an initial loading dose?
● What was the patient’s digoxin serum concentration level?
● When was the digoxin level measured?
● How soon after taking the double dose pill did symptoms of digoxin intoxication develop?
● Was there a diagnosis of digoxin intoxication?
● What non-cardiac symptoms, if any, did the patient have?
● Did the patient suffer from renal failure or deficiency?
● What other drugs was the patient taking?
● Is there any evidence the patient was given treatment for digoxin toxicity such as administration of activated charcoal or digoxin-specific antibody fragments (Digibind or DigiFab).
● If the patient died, what was the listed cause of death?
● How old was the patient?
"Heygood, Orr, Reyes, Pearson & Bartolomei is a business litigation and personal injury law firm, based in Dallas, Texas. We have worked with executives, business owners, and individuals to try over 300 cases to a jury verdict."
The firm is a drug known as Digitek.
Eric Pearson's report - it's copyrighted:
Digitek is the trade name for digoxin tablets manufactured in the United States by Actavis Totowa, LLC, the U.S. manufacturing division of international generic pharmaceutical company Actavis Group. The tablets are distributed in the U.S. by Mylan Pharmaceuticals, based in Morgantown, West Virginia and by UDL Laboratories, based in Rockford, Illinois. Both Mylan Pharmaceuticals and UDL are owned by parent company Mylan, a drug company based in Pittsburgh, Pennsylvania with a market cap of $4 billion. The tablets are distributed by Mylan under a “Bertek” label and by UDL under a “UDL” label. It appears that the tablets distributed under the UDL label are distributed to hospitals and other health care facilities in unit dose form in a foil blister pack. The tablets distributed by Mylan under the Bertek label are believed to have been distributed in standard pill bottles.
The Digitek tablets are manufactured by Actavis Totowa in their Elizabeth, New Jersey plant. Their website describes the plant as a “solid-oral-does facility for tablets and capsules supporting a broad therapeutic range” with a “core competency on modified-release products.” The FDA has a different take on the competency of this facility. As set forth in the Warning Letter attached hereto as Exhibit A, the FDA conducted a plant inspection from January 10 through February 6, 2006 and found numerous issues of concern, including:
● Failure to submit required FDA Adverse Drug Experience (“ADE”) Reports;
● Failure to promptly investigate serious and unexpected ADE reports;
● Failure to ever file a required Periodic Safety Report;
● Manufacturing numerous prescription drug products without approved applications.
Digitek was approved by the FDA through a process known as an Abbreviated New Drug Application (“ANDA”). An ANDA applies to a generic equivalent of a prescription drug that has already received FDA approval. The already-approved drug on which Actavis based its ANDA was Lanoxin, a digoxin tablet manufactured by GlaxoSmithKline. In order to secure FDA approval, Actavis was required to demonstrate that its Digitek tablets were “bioequivalent” in comparison to Lanoxin. Bioequivalence factors scrutinized by the relevant authorities concern active ingredient(s), quality, safety, dosage forms and strengths, performance characteristics and intended use. Actavis’ ANDA No. 40-282 was approved by the FDA by letter dated December 23, 1999.
III. The Digitek recall.
On April 25, 2008, Actavis announced a recall of all lots of Bertek and UDL Laboratories Digitek tablets. According to its Press Release, attached hereto as Exhibit B, Actavis initiated the voluntary all-lot recall because “due to the possibility that tablets with double the appropriate thickness may have been commercially released.” Actavis further stated that “[t]hese tablets may contain twice the approved level of active ingredient than is appropriate.” Further, according to the Actavis Press Release:
The existence of double strength tablets poses a risk of digitalis toxicity in patients with renal failure. Digitalis toxicity can cause nausea, vomiting, dizziness, low blood pressure, cardiac instability and bradycardia. Death can also result from excessive Digitalis intake. Several reports of illnesses and injuries have been received.
IV. Dosing issues.
Digitek tablets are sold in two doses, .125 mg and .25 mg. A study of patients given a single .25 mg daily dose of digoxin showed a median digoxin concentration level of .9 ng/mL for women and .8 ng/mL for men. Rathore, Sex-Based differences in the Effect of Digoxin for the Treatment of Heart Failure. Long-term results from the same study showed a mean digoxin concentration of .97 to 1.01 ng/mL between all sexes. Id. Similar data was obtained from a large scale study completed in 1997. Among 1485 patients, the mean digoxin level for patients taking a .25 mg tablet was .89 ng/mL.”). The Digitalis Investigation Group, The Effect of Digoxin on Mortality and Morbidity in Patients With Heart Failure. That same study showed a mean digoxin level for patients taking a .125 mg tablet of .76 ng/mL. Id.
According to data provided to the FDA in Actavis’ NDA, a patient given two of the .25 mg tablets will typically have an immediate mean serum concentration level of between 1.8 ng/mL and 2.0 ng/mL. The concentration level is expected to rapidly decline to a level of less than .6 ng/mL within six to eight hours.
According to information provided to the FDA by the makers of Lanoxin, about two-thirds of adult patients considered adequately dosed with digoxin (and without evidence of toxicity) have serum digoxin concentrations ranging from .8 to 2.0 ng/mL. About two-thirds of patients suffering from digitalis toxicity have serum digoxin concentrations above 2.0 ng/mL while one-third have levels below 2.0 ng/mL.
According to Baselt, Disposition of Toxic Drugs and Chemicals in Man, Seventh Edition, peak serum concentrations of digoxin measured in a variety of clinical tests ranged from 1.13 ng/mL to 2.4ng/mL depending on dosage. Baselt also states that one study of 48 patients exhibiting signs of digoxin toxicity found average serum concentrations of digoxin of 3.7 ng/mL with a range from 1.6 ng/mL to 13.7 ng/mL. another study of some 1000 patients found a mean serum digoxin level in nontoxic patients of 1.4 ng/mL. Bhatia, Digitalis Toxicity—Turning Over a New Leaf. Although the serum digoxin level in patients with toxicity was two to three times higher, “there was considerable overlap between the two groups of patients.” Id.
The foregoing data demonstrates that digoxin has a very narrow therapeutic range. As one medical publication has explained:
Digoxin has a narrow therapeutic window: that is to say, there is only a small range of plasma concentration between the drug being ineffective through underdosing, and toxic through overdosing.
This conclusion has been borne out by a variety of studies found in the medical literature. See, e.g., THCP Education Consortium, Digoxin Toxicity (“There is a narrow therapeutic range for digoxin – which means that the patient can easily have too much or too little of the drug on board.”). Based on the available literature, it appears clear that a double dose of digoxin could lead to digoxin toxicity.
V. Possible side effects of digoxin use.
According to the Lanoxin Product Insert (which is identical to the Digitek product insert), attached hereto as Exhibit C, various side effects may arise from the use of digoxin. Adverse reactions are generally dose-dependent. Exhibit C at p. 7. In the past, approximately one-half of all adverse reactions were cardiac in nature. Id. One-fourth of all adverse reactions were gastrointestinal and the final one-fourth were related to the central nervous system (“CNS”).
A.Cardiac events.
As stated above, about one-half of previously reported adverse events were cardiac in nature. According to the product insert, among the cardiac problems that may be caused from a high dose of digoxin are the following:
first-degree, second-degree (Wenckebach) or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation.
Exhibit C at p. 7. Baselt, Disposition of Toxic Drugs and Chemicals in Man, Seventh Edition, lists possible cardiac side effects as “cardiac disturbances such as tachycardia, premature contractions, atrial fibrillation and atrioventricular block.” Manifestations of these cardiac events include palpitations, loss of consciousness and difficulty breathing.
B.Gastrointestinal events.
Gastrointestinal events caused by digoxin may include anorexia, nausea, vomiting and diarrhea. Other, less frequent, events include abdominal pain, intestinal ischemia and hemorrhagic necrosis of the intestines.
C.Central nervous system and other adverse events.
Events related to the central nervous system include visual disturbances such as blurred or yellow vision, headaches, weakness, dizziness, apathy and confusion. Other possible side effects include mental disturbances such as anxiety, depression, delirium and hallucinations. Gynecomastia, or breast enlargement in males, has also been reported.
VI. Digoxin toxicity.
A.General principles.
Digitek tablets are sold in two doses, .125 mg and .25 mg. A patient given two of the .25 mg tablets will typically have an immediate mean serum concentration level of between 1.8 ng/mL and 2.0 ng/mL. According to information provided to the FDA by the makers of Lanoxin, about two-thirds of adult patients considered adequately dosed with digoxin (and without evidence of toxicity) have serum digoxin concentrations ranging from .8 to 2.0 ng/mL. According to Baselt, Disposition of Toxic Drugs and Chemicals in Man, Seventh Edition, peak serum concentrations of digoxin measured in a variety of clinical tests ranged from 1.13 ng/mL to 2.4ng/mL depending on dosage.
While the highest strength Digitek tablet is .25 mg, Lanoxin used to be prescribed in doses up to .5 mg. In fact, when Actavis did testing of their .25 mg pill, they gave the subjects two of the pills (or .5 mg) because they were attempting to replicate studies that GlaxoSmithKline had done on their .5 mg pills. Thus, a patient taking one .25 mg Digitek tablet that contained a double dose of digoxin would arguably be expected to achieve the same digoxin serum level as did those patients in the clinical trials conducted by Actavis: a mean serum concentration level of between 1.8 ng/mL and 2.0 ng/mL.
Unfortunately, there are many problems with drawing a bright-line rule from the available data and studies. First, the effects of digoxin are highly variable among patients. Second, the narrow therapeutic range of digoxin makes it difficult to determine whether a particular digoxin level is therapeutic or toxic in a particular patient:
Considering there is some overlap between therapeutic and toxic serum digoxin levels, symptoms of toxicity may be reported in patients whose levels are within the therapeutic range, while others may have no symptoms hen their serum digoxin levels are above the therapeutic threshold.
Hixson-Wallace, Digoxin Toxicity: A Review. Finally, digoxin levels taken less than 6 hours after the administration of digoxin may overstate the true digoxin level. See Williamson, Digoxin Toxicity: An Evaluation in Current Clinical Practice. As stated in the Lanoxin Product Insert:
Following drug administration, a 6- to 8-hour distribution phase is observed. . . . clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action . . . . To allow adequate time for equilibration of digoxin between serum and tissue, sampling of serum concentrations should be done just before the next scheduled dose of the drug. If this is not possible, sampling should be done at least 6 to 8 hours after the last dose, regardless of the route of administration or the formula used.
Exhibit C at pp. 3, 9. When reviewing any digoxin serum concentration level, it is important to know when it was drawn relative to the ingestion of digoxin.
B.Digoxin levels as a predictor of digoxin toxicity.
Despite the foregoing issues, properly obtained digoxin levels remain the best indicator of digoxin toxicity. A digoxin level of 3.0 ng/mL or greater is a strong predictor of digoxin toxicity:
Baselt states that one study of 48 patients exhibiting signs of digoxin toxicity found average serum concentrations of digoxin of 3.7 ng/mL.
Another study of some 1000 patients found a mean serum digoxin level in patients suffering from digoxin toxicity of 2.8 ng/mL to 4.2 ng/mL. Bhatia, Digitalis Toxicity—Turning Over a New Leaf.
A study of nearly 800 patients in Japan found that all patients with a digoxin level over 3.0 ng/mL exhibited clinical evidence of digoxin toxicity.” Miura, Effect of Aging on the Incidence of Digoxin Toxicity.
One study showed that “the risk of toxicity at a digoxin concentration of higher than 3.0 ng/mL was 12-fold the risk of at a serum concentration of 0 to .99 ng/mL.” Bhatia, Digitalis Toxicity—Turning Over a New Leaf.
A study of more than 2000 patients found that the mean digoxin serum concentration level for patients with definite digoxin toxicity was 3.6 ng/mL and the mean level for patients with possible digoxin toxicity was 3.4 ng/mL. Williamson, Digoxin Toxicity: An Evaluation in Current Clinical Practice.
One author has concluded that “although no serum digoxin level proves or disproves toxicity, a level higher than 3.0 ng/mL in the appropriate setting lend strong support to diagnosis of digitalis excess.” Bhatia, Digitalis Toxicity—Turning Over a New Leaf.
A digoxin level greater than 2.0 ng/mL is also a fair predictor of digoxin intoxication. A study from North Carolina showed that 60% of patients with a digoxin level over 2.0 ng/mL that was measured more than 6 hours after administration of digoxin had clinical evidence of digoxin toxicity. Williamson, Digoxin Toxicity: An Evaluation in Current Clinical Practice.
A digoxin level below 2.0 ng/mL is a possible indicator of digoxin toxicity. Anywhere from 10% to 33% of patients with such a level may experience adverse side effects as a result of digoxin toxicity:
One study of some 1000 patients showed that 10% of patents with digoxin toxicity had serum concentrations of less than 2.0 ng/mL. Smith, Digitalis Glycosides: Mechanism and Manifestation of Toxicity.
As stated in the Lanoxin Product Insert: “since one-third of patients with clinical toxicity have serum digoxin concentrations less than 2.0 ng/mL, values below 2.0 ng/mL do not rule out the possibility that a certain sign or symptom is related to digoxin therapy.”
A study in Japan “showed that there was an overlapping (toxic and nontoxic) range of serum digoxin concentrations in which the incidence of digoxin toxicity was patient dependent (1.4 – 2/9 ng/mL).” Miura, Effect of Aging on the Incidence of Digoxin Toxicity.
Baselt states that one study of 48 patients exhibiting signs of digoxin toxicity found average digoxin serum concentrations ranging from 1.6 to 13.7 ng/mL.
Another study of some 1000 patients found “considerable overlap” in the digoxin serum concentration levels of nontoxic and toxic patients. Bhatia, Digitalis Toxicity—Turning Over a New Leaf.
Clearly, there will be many patients --- perhaps between 10 and 33% -- with a digoxin level below 2.0 ng/mL who will suffer the effects of digoxin toxicity.
C.At-risk patients.
Of course, certain patients are more susceptible to digoxin toxicity, and the above conclusions do not apply to those patients. This includes elderly patients. See Schreiber, Digitalis Toxicity (“Advanced age (>80) is an independent risk factor and is associated with increased morbidity and mortality.”); Miura, Effect of Aging on the Incidence of Digoxin Toxicity (“clinical evidence of digoxin toxicity in patients > 71 years old was 26.5%, despite their SDCs falling between 1.4 and 2.0 ng/mL . . . . “[t]his raises the possibility that patients > 71 years show clinical evidence of digoxin toxicity despite having SDCs within the recommended therapeutic range.”).
Patients who have previously suffered from renal failure are also particularly susceptible to digoxin toxicity. Exhibit C at p. 5 (“[i]f appropriate care is not taken to reduce the dose of digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function.”). Other at-risk patients are those with electrolyte disorders such as hypokalemia (low blood potassium), hypomagnesemia (magnesium deficiency) or hypocalcemia (low blood calcium levels). Exhibit C at p. 5. Patients with thyroid disorders are also especially at risk. Exhibit C at p. 5.
D.Symptoms of digoxin toxicity.
Although increased digoxin levels may be a good predictor of digoxin toxicity, the ultimate issue from a damage perspective is whether a patient suffered any injury because of digoxin toxicity. As one author has noted, “clinically stable patients receiving digoxin who have elevated SDCs but are without signs or symptoms of digoxin toxicity are at low risk of developing serious digoxin toxicity and do not generally require treatment beyond the discontinuation of digoxin therapy.” Park, Digoxin Toxicity in Patients with High Serum Digoxin Concentrations. Thus, it is important to be aware of the most prevalent symptoms of digoxin toxicity.
1.Cardiac events.
Increased congestive heart failure may be the initial manifestation of digitalis toxicity in as many as 7.5% of patients. Dysrhythmia, or an abnormal heart rate, occurs in 80% to 90% of patients with digitalis toxicity. Bhatia, Digitalis Toxicity—Turning Over a New Leaf. Perhaps the earliest cardiac manifestation of digoxin toxicity in many patients is premature ventricular contraction (”PVC”). The Digitalis Investigation Group, The Effect of Digoxin on Mortality and Morbidity in Patients With Heart Failure. Ventricular fibrillation and tachycardia are also common symptoms.
The type of arrhythmia will often indicate whether a cardiac event has been caused by digitalis toxicity. Among the types of arrhythmias most suggestive of digitalis toxicity are the following:
● Bidirectional ventricular tachycardia
● Bigeminal ventricular Rhythm
● Multiform premature ventricular complexes
● Atrial tachycardia with block
● Nonparoxysmal AV junctional tachycardia
● Supraventricular rhythm (atrial fibrillation) with ventricular ectopy
● Nonconducted premature atrial complexes
● Ventricular tachycardia with exit block
Bhatia, Digitalis Toxicity—Turning Over a New Leaf. HJJ Wellens has developed four criteria for the electrocardiographic diagnosis of digitalis toxicity. They are:
1.Appearance of a slow heart rate in a patent with a fast or normal heart rate;
2.Appearance of a fast heart rate in a patient with a normal heart rate;
3.Appearance of a regular heart rhythm in a patient with an irregular rhythm; and
4.Appearance of a regularly irregular rhythm.
Wellens, HHJ, The Electrocardiogram in Digitalis Intoxication. Other authors suggest that the most common EKG changes in digoxin toxicity are PR-segment prolongation and cupping of the ST segment. Another author has stated that the typical “digitalis effect” found in electrocardiogram readings are manifested by a shortened QT interval and a characteristic down-sloping ST depression with the T wave opposite in polarity to the QRS complex. TCHP Education Consortium, Digoxin Toxicity.
2.Other events.
The first symptoms of digitalis are often gastrointestinal – anorexia, nausea, vomiting, and diarrhea. THCP Edcuation Consortium, Digoxin Toxicity. The most common symptom associated with digoxin toxicity is nausea. Williamson, Digoxin Toxicity: An Evaluation in Current Clinical Practice. Other, non-cardiac events associated with digoxin toxicity include:
● fatigue
● dizziness
● confusion
● delirium
● blurred vision
● disturbed color perception
● hallucinations
● abdominal pain
● headaches
The most common vital sign abnormality is bradycardia.
3.Death.
According to the Lanoxin Product Insert, “manifestations of life-threatening toxicity include ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhymthias, or heart block.” Exhibit C at p. 8. The Product Insert also states that “the administration of more than 10 mg of dioxin in a previously healthy adult . . . often results in cardiac arrest.” Id. Of course, this information is of limited utility because most patients taking dioxin tablets already suffer from some type of heart problem and cannot be considered “healthy adults.” As a result, they are more susceptible to cardiac arrest. This fact also complicates the diagnosis of cardiac events attributable to digitalis toxicity.
A 2005 study by K.F. Adams and others “demonstrated a significant linear relationship between serum digoxin concentration and mortality.” Adams, Relationship of Serum Digoxin Concentration to Mortality. According to a 1997 study by the American Association of Poison Control Centers, of the patients who reported digitalis toxicity, approximately 1% died. Another study showed that 3 of 20 (15%) of patients diagnosed with digoxin toxicity died despite appropriate intervention. Williamson, Digoxin Toxicity: An Evaluation in Current Clinical Practice. The Emergency Response Card for Digoxin published by the National Institute for Occupational Safety and Health states that severe exposures to digoxin may result in death, Perhaps most importantly, in its Recall Notice submitted to the FDA, Actavis stated that “[d]eath can result from excessive digitalis intake.” Exhibit B. Clearly, digitalis toxicity can lead to death.
Some of the predictors of whether digoxin toxicity can cause death are the serum digoxin concentration and the age of the patient. My compilation and analysis of data from the last five years of the Annual Report of the American Association of Poison Control Centers’ National Poison Data System yielded valuable insight into these predictors. According to the data, the mean serum digoxin level of patients who died from digoxin toxicity was 4.27 ng/mL. Further, 75% of fatalities from digoxin toxicity occurred with digoxin levels of 3.0 ng/mL or greater. With respect to age, the mean age of a patient judged to have died from digoxin toxicity was 78.5 years. Nearly 80% of all digoxin toxicity fatalities occurred in patients aged 70 years or older. None occurred in patients under the age of 60.
Finally, it is stating the obvious to note that the more pills a patient is taking, the greater the likelihood that a double-dose pill would cause death due to digoxin toxicity. Digitek is manufactured in .125 and .25 mg tablets. A typical daily therapeutic dose is .25 mg. However, patients are sometimes instructed to take several tablets per day in order to reach the desired digoxin level. As set forth in the Lanoxin Product Insert, “if rapid digitialization is considered medically appropriate, it may be achieved by administering a loading dose based upon projected peak digoxin body stores.” Exhibit C at p. 10 (“digitalization” simply refers to the use of digitalis glycosides such as dioxin to treat heart failure). Although the Lanoxin Product Insert provides information regarding an appropriate “loading dose,” it does so only with respect to digoxin injections. Medical literature, however, suggests that an appropriate loading does for digoxin tablets would an initial dose of .5 mg followed by additional doses of .25 mg to .5 mg every 6 hours until digitalization is achieved. Arnsdorf, Method of Digitalization. The total oral dose needed for digitalization is typically 1 to 2 mg using oral digoxin tablets.
Thus, in patients where rapid digitalization has been ordered, the patient may take up to 2 mg of digoxin tablets in one 24-hour period. Patients taking multiple doses of Digitek during a 24-hour period are much more likely to suffer a fatal digoxin overdose from a double-strength pill than those taking one .125 or .25 mg pill per day. We should therefore be on the lookout for injuries and deaths suffered by patients undergoing an initial “loading dose” of Digitek.
VII. What to look for in a case.
Given all of the above, what questions should an attorney ask when assessing potential cases against Actavis as a result of a double-dose of Digitek?
● Does the patient have the pills?
● What strength pills were prescribed?
● How frequently were they taking the pills?
● Was the patient in the middle of an initial loading dose?
● What was the patient’s digoxin serum concentration level?
● When was the digoxin level measured?
● How soon after taking the double dose pill did symptoms of digoxin intoxication develop?
● Was there a diagnosis of digoxin intoxication?
● What non-cardiac symptoms, if any, did the patient have?
● Did the patient suffer from renal failure or deficiency?
● What other drugs was the patient taking?
● Is there any evidence the patient was given treatment for digoxin toxicity such as administration of activated charcoal or digoxin-specific antibody fragments (Digibind or DigiFab).
● If the patient died, what was the listed cause of death?
● How old was the patient?
Total Body Formula Recall Makes News In Georgia Paper
My office has filed several lawsuits - NOT a class action - involving the Total Body Formula and Total Body Mega Formula recall.
In March, the FDA had warned consumers not to purchase or consume Total Body Formula in the flavors of Tropical Orange and Peach Nectar, or Total Body Mega Formula in the Orange/Tangerine flavor. The liquid dietary supplement products may cause severe adverse reactions, including significant hair loss, muscle cramps, diarrhea, joint pain and fatigue.
From an Athens, Georgia paper there was an article regarding the recalled products. The article refers to Total Body Formula as a "diet aid," although I would not have used those two words to describe the product.
More here.
In March, the FDA had warned consumers not to purchase or consume Total Body Formula in the flavors of Tropical Orange and Peach Nectar, or Total Body Mega Formula in the Orange/Tangerine flavor. The liquid dietary supplement products may cause severe adverse reactions, including significant hair loss, muscle cramps, diarrhea, joint pain and fatigue.
From an Athens, Georgia paper there was an article regarding the recalled products. The article refers to Total Body Formula as a "diet aid," although I would not have used those two words to describe the product.
More here.
Gardisil: Problems Looming?
From a news website:
Gardisil is a vaccine given to protect women against certain types of cervical cancer.
There have been complaints of paralysis, blood clots and death. The Centers for Disease Control and Prevention has recently stated that despite the complaint, none of the side effects can be linked to Gardasil.
From another site:
"Lisa Ericzon tells the New York Post that her daughter Jessica received her third dose of the vaccine on February 20th of last year. Ericzon says in the article that two days late, her daughter collapsed and died and she says her daughter had complained of pain in the back of her head following both the second and third vaccine shots. An autopsy could not determine the cause of death.
Merck, the company that makes Gardasil, says the New York Post never contacted them for comment on the story. The FDA, CDC and State Health Department continue to recommend Gardasil." Source.
For more go here.
Gardisil is a vaccine given to protect women against certain types of cervical cancer.
There have been complaints of paralysis, blood clots and death. The Centers for Disease Control and Prevention has recently stated that despite the complaint, none of the side effects can be linked to Gardasil.
From another site:
"Lisa Ericzon tells the New York Post that her daughter Jessica received her third dose of the vaccine on February 20th of last year. Ericzon says in the article that two days late, her daughter collapsed and died and she says her daughter had complained of pain in the back of her head following both the second and third vaccine shots. An autopsy could not determine the cause of death.
Merck, the company that makes Gardasil, says the New York Post never contacted them for comment on the story. The FDA, CDC and State Health Department continue to recommend Gardasil." Source.
For more go here.
Friday, July 25, 2008
Epilepsy Drug May Increase Risk of Birth Defects
So says the American Academy of Neurology (find more here):
Taking the epilepsy drug topiramate alone or along with other epilepsy drugs during pregnancy may increase the risk of birth defects, according to a study published in the July 22, 2008, issue of Neurology®, the medical journal of the American Academy of Neurology.
Research has shown that many epilepsy drugs increase the risk of birth defects, but little research has been done on topiramate. Studies have shown that topiramate increases the risk of birth defects in animals. Maintaining effective epilepsy treatment during pregnancy is crucial because seizures may cause harm to the fetus.
For the study, researchers examined women who became pregnant while taking topiramate either on its own or along with other epilepsy drugs. Of 178 babies born, 16 had major birth defects. Three of these were in infants whose mothers were taking only topiramate, and 13 were in those whose mothers were taking topiramate and other epilepsy drugs.
Taking the epilepsy drug topiramate alone or along with other epilepsy drugs during pregnancy may increase the risk of birth defects, according to a study published in the July 22, 2008, issue of Neurology®, the medical journal of the American Academy of Neurology.
Research has shown that many epilepsy drugs increase the risk of birth defects, but little research has been done on topiramate. Studies have shown that topiramate increases the risk of birth defects in animals. Maintaining effective epilepsy treatment during pregnancy is crucial because seizures may cause harm to the fetus.
For the study, researchers examined women who became pregnant while taking topiramate either on its own or along with other epilepsy drugs. Of 178 babies born, 16 had major birth defects. Three of these were in infants whose mothers were taking only topiramate, and 13 were in those whose mothers were taking topiramate and other epilepsy drugs.
Friday Tech: Searching All Craigslist Sites
Craigslist.org is a website that at least in Atlanta is to me the best free version of classified ads around. I've been able to find a vehicle, temporary office workers, concert tickets, and a desk on it. In other cities I have found affordable by owner short term rentals, and even auto parts.
As useful as the site is, however, to me it was almost impossible to search all cities on Craigslist. From Lifehacker comes a solution (via wired.com):
Google's Advanced Search yields a way to limit results to domains, such as Craigslist.org. Advanced Search is the link located right next to the main search field on Google’s home page. Click on "Advanced Search" and follow the directions on the link posted above.
There is a shorthand method
* Type in the search field:
site:craigslist.org “antique coastal surveys ”
With or without quotes to broaden or narrow down the search.
* You can also use booleans to modify the range of your search:
site:craigslist.org antique|vintage coastal surveys
As useful as the site is, however, to me it was almost impossible to search all cities on Craigslist. From Lifehacker comes a solution (via wired.com):
Google's Advanced Search yields a way to limit results to domains, such as Craigslist.org. Advanced Search is the link located right next to the main search field on Google’s home page. Click on "Advanced Search" and follow the directions on the link posted above.
There is a shorthand method
* Type in the search field:
site:craigslist.org “antique coastal surveys ”
With or without quotes to broaden or narrow down the search.
* You can also use booleans to modify the range of your search:
site:craigslist.org antique|vintage coastal surveys
Thursday, July 24, 2008
Vytorin: Dear Doctor Letter Readied
Vytorin is a drug made by a partnership of Merck & Schering-Plough. There's news that a letter has been readied to be sent to doctor who may be asking about recently released study results that showed patients taking the cholesterol drug were at higher risk of dying from cancer.
Video (less than 90 seconds)here: http://www.cnbc.com/id/15840232?video=801729653
From various sites:
The companies will take the stance that the increase in cancer deaths and higher incidence of cancer in a recent study involving 1,873 people should be considered an anomaly. The SEAS study were released this week, and it is in that study that the cancer connection is alleged. Source.
What is SEAS? It is the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. It is a randomized, multicenter, placebo-controlled study evaluating the effects of combination ezetimibe/simvastatin (Vytorin) on clinical outcomes in roughly 1800 patients with aortic stenosis, and the results showed that the controversial cholesterol-lowering medication was no better than placebo in reducing the primary composite end point of aortic-valve and cardiovascular events. (Link)
Other sites note this:
What Do the SEAS Results Mean?
There was speculation that the trial could help rehabilitate Vytorin after the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial was published in March, but the placebo-controlled trial design, as well as the patient population, were likely to limit the clinical impact.
The SEAS results are the first clinical results for Vytorin since ENHANCE was published. In that study, investigators tested the effectiveness of combined ezetimibe/simvastatin therapy in patients with familial hypercholesterolemia and found that the combination did no better than simvastatin monotherapy on several surrogate end points. The combination did not result in a significant difference in changes in intima-media thickness compared with simvastatin alone, despite significantly greater reductions in LDL cholesterol and C-reactive protein.(Link).
Video (less than 90 seconds)here: http://www.cnbc.com/id/15840232?video=801729653
From various sites:
The companies will take the stance that the increase in cancer deaths and higher incidence of cancer in a recent study involving 1,873 people should be considered an anomaly. The SEAS study were released this week, and it is in that study that the cancer connection is alleged. Source.
What is SEAS? It is the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. It is a randomized, multicenter, placebo-controlled study evaluating the effects of combination ezetimibe/simvastatin (Vytorin) on clinical outcomes in roughly 1800 patients with aortic stenosis, and the results showed that the controversial cholesterol-lowering medication was no better than placebo in reducing the primary composite end point of aortic-valve and cardiovascular events. (Link)
Other sites note this:
What Do the SEAS Results Mean?
There was speculation that the trial could help rehabilitate Vytorin after the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial was published in March, but the placebo-controlled trial design, as well as the patient population, were likely to limit the clinical impact.
The SEAS results are the first clinical results for Vytorin since ENHANCE was published. In that study, investigators tested the effectiveness of combined ezetimibe/simvastatin therapy in patients with familial hypercholesterolemia and found that the combination did no better than simvastatin monotherapy on several surrogate end points. The combination did not result in a significant difference in changes in intima-media thickness compared with simvastatin alone, despite significantly greater reductions in LDL cholesterol and C-reactive protein.(Link).
Wednesday, July 23, 2008
Truck driving while disabled: 'Major public safety problem'
From the Atlanta Journal Constitution comes news that thousands of drivers hold commercial licenses even though they also qualify for full federal disability payments.
From the article:
"The problems threatening highway travelers persist despite years of government warnings and hundreds of deaths and injuries blamed on commercial truck and bus drivers who blacked out, collapsed or suffered major health problems behind the wheels of vehicles that can weigh 40 tons or more. Georgia is among 12 states where drivers are sanctioned most often for violating medical rules."
The eye opener quote: "We have a major public safety problem, and we haven't corrected it," - says Gerald Donaldson. Donaldso is a director at the Washington-based Advocates for Highway and Auto Safety.
For more, go here.
From the article:
"The problems threatening highway travelers persist despite years of government warnings and hundreds of deaths and injuries blamed on commercial truck and bus drivers who blacked out, collapsed or suffered major health problems behind the wheels of vehicles that can weigh 40 tons or more. Georgia is among 12 states where drivers are sanctioned most often for violating medical rules."
The eye opener quote: "We have a major public safety problem, and we haven't corrected it," - says Gerald Donaldson. Donaldso is a director at the Washington-based Advocates for Highway and Auto Safety.
For more, go here.
Thursday, July 17, 2008
Avastin Tied to Anemia
From various sources, including CNN:
The FDA has, this week, issued an alert regarding cancer drug Avastin. There has been an alleged link to the development of anemia in several patients.
According to the FDA, patients have reported that when Avastin was taken in combination with Sutent, another cancer drug, reported microangiopathic hemolytic anemia (a loss of red blood cells).
What is particularly important is that Avastin is not approved to be taken in combination with Sutent, a cancer drug manufactured by Pfizer.
Here's the link.
The FDA has, this week, issued an alert regarding cancer drug Avastin. There has been an alleged link to the development of anemia in several patients.
According to the FDA, patients have reported that when Avastin was taken in combination with Sutent, another cancer drug, reported microangiopathic hemolytic anemia (a loss of red blood cells).
What is particularly important is that Avastin is not approved to be taken in combination with Sutent, a cancer drug manufactured by Pfizer.
Here's the link.
Sunday, July 13, 2008
FDA Requests Boxed Warnings on Fluoroquinolone Antimicrobial Drugs
From the FDA site for these listed drugs:Cipro and generic ciprofloxacin, Cipro XR and Proquin XR (ciprofloxacin extended release), Factive (gemifloxacin), Levaquin (levofloxacin), Avelox (moxifloxacin), Noroxin (norfloxacin), and Floxin and generic ofloxacin.
The Release:
The U.S. Food and Drug Administration (FDA) has notified manufacturers of fluoroquinolone antimicrobial drugs that a Boxed Warning in the product labeling concerning the increased risk of tendinitis and tendon rupture is necessary. Through its new authority under the Food and Drug Administration Amendments Act of 2007 (FDAAA), the agency also determined that it is necessary for manufacturers of the drugs to provide a Medication Guide to patients about possible side effects.
The FDA has notified the manufacturers of these drugs that a Risk Evaluation and Mitigation Strategy (REMS) is necessary to ensure that the benefits of the drug outweigh the risks. The Medication Guide will be considered to be an element of the REMS. The new Boxed Warning and Medication Guide would strengthen warning information already included in product labeling for the fluoroquinolone class of systemic antimicrobial drugs.
Fluoroquinolones are drugs approved for the treatment or prevention of certain bacterial infections. Like other antibacterial drugs, fluoroquinolones do not treat viral infections such as colds or flu.
"Fluoroquinolones are effective in treating certain bacterial infections, but health care professionals and patients need to be aware of the increased risk associated with the use of these drugs of developing tendinitis and tendon rupture, particularly for certain patient populations," said Edward Cox, M.D., director, Office of Antimicrobial Products, Center for Drug Evaluation and Research. "The FDA believes it is important to highlight and strengthen information regarding possible side effects of fluoroquinolones because it may affect decisions about the relative risks and benefits associated with these products."
The FDA has conducted a new analysis of the available literature and post-marketing adverse event reports. This new analysisreconfirmsthat use of fluoroquinolones is associated with an increased risk of tendon rupture. It alsodemonstrates that despite the current warning of tendon rupture in the labeling for the fluoroquinolones, large numbers of tendon-related adverse events continue to be reported. The FDA considers this new analysis to be "new safety information" as defined in FDAAA.
Link here.
The Release:
The U.S. Food and Drug Administration (FDA) has notified manufacturers of fluoroquinolone antimicrobial drugs that a Boxed Warning in the product labeling concerning the increased risk of tendinitis and tendon rupture is necessary. Through its new authority under the Food and Drug Administration Amendments Act of 2007 (FDAAA), the agency also determined that it is necessary for manufacturers of the drugs to provide a Medication Guide to patients about possible side effects.
The FDA has notified the manufacturers of these drugs that a Risk Evaluation and Mitigation Strategy (REMS) is necessary to ensure that the benefits of the drug outweigh the risks. The Medication Guide will be considered to be an element of the REMS. The new Boxed Warning and Medication Guide would strengthen warning information already included in product labeling for the fluoroquinolone class of systemic antimicrobial drugs.
Fluoroquinolones are drugs approved for the treatment or prevention of certain bacterial infections. Like other antibacterial drugs, fluoroquinolones do not treat viral infections such as colds or flu.
"Fluoroquinolones are effective in treating certain bacterial infections, but health care professionals and patients need to be aware of the increased risk associated with the use of these drugs of developing tendinitis and tendon rupture, particularly for certain patient populations," said Edward Cox, M.D., director, Office of Antimicrobial Products, Center for Drug Evaluation and Research. "The FDA believes it is important to highlight and strengthen information regarding possible side effects of fluoroquinolones because it may affect decisions about the relative risks and benefits associated with these products."
The FDA has conducted a new analysis of the available literature and post-marketing adverse event reports. This new analysisreconfirmsthat use of fluoroquinolones is associated with an increased risk of tendon rupture. It alsodemonstrates that despite the current warning of tendon rupture in the labeling for the fluoroquinolones, large numbers of tendon-related adverse events continue to be reported. The FDA considers this new analysis to be "new safety information" as defined in FDAAA.
Link here.
Botox News: Lawsuits Filed
A number of Botox users and relatives of those who had the drug administered filed suit in California, claiming that the drug injured or killed. The maker of the drug, Allergan Inc. is the company, and the company is based in Califoria.
Cases include one where an over 60 nurse allegedly died after receiving injections for neck and shoulder pain. Another involves a child with cerebral palsy, also from Texas, who died in 2004, allegedly after receiving injections to control limb spasticity.
Source here.
Perhaps the most famous claimed user of Botox to address spasticity is Robert F. Kennedy Jr. Kennedy is is said has a condition called spasmodic dysphonia, a specific form of an involuntary movement disorder called dystonia that affects only the voice box.
Cases include one where an over 60 nurse allegedly died after receiving injections for neck and shoulder pain. Another involves a child with cerebral palsy, also from Texas, who died in 2004, allegedly after receiving injections to control limb spasticity.
Source here.
Perhaps the most famous claimed user of Botox to address spasticity is Robert F. Kennedy Jr. Kennedy is is said has a condition called spasmodic dysphonia, a specific form of an involuntary movement disorder called dystonia that affects only the voice box.
No Blackbox Warnings for Epilepsy Drugs
From various sources comes the news that anti-seizure drugs may allegedly cause increased suicidal tendencies in patients. Even so, it's not enough to result in the FDA imposition of the strongest warning label on them, according to the FDA law week.
A 20 member FDA panel vote unanimously to back findings on a number of antiepileptic drugs studied. Back at the start of 2008, FDA informed there could be a black box warning added after a study of 199 studies comparing the drugs, which are used by millions, to placebos.
For more, go here.
A 20 member FDA panel vote unanimously to back findings on a number of antiepileptic drugs studied. Back at the start of 2008, FDA informed there could be a black box warning added after a study of 199 studies comparing the drugs, which are used by millions, to placebos.
For more, go here.
Tuesday, July 01, 2008
Verdict in AWP Case in Alabama: $100 Million +
Tom Methvin's law firm in Montgomery rendered a verdict for the State of Alabama yesterday.
Pharmaceutical companies charged for drugs based on the Average Wholesale Price (AWP). Average Wholesale Price” or AWP has long been used as a pricing benchmark for almost all prescription drug sales in the United States. Health plans, Medicaid and other government programs, and employers determine how much to pay pharmacies and doctors to reimburse them for drugs that are dispensed to patients by using formulas based on the AWP for individual drugs. Source.
A jury in Montgomery County Circuit Court returned a verdict in favor of the State of Alabama in a case involving AWP and allegations of fraud, finding defendants GlaxoSmithKline and Novartis Pharmaceuticals Corp. liable for a total of $114,247,233, of which $80,989,539 is from GlaxoSmithKline and $33,257,694 is from Novartis.
For more on Tom's Firm's victory for the State of Alabama, go here.
Pharmaceutical companies charged for drugs based on the Average Wholesale Price (AWP). Average Wholesale Price” or AWP has long been used as a pricing benchmark for almost all prescription drug sales in the United States. Health plans, Medicaid and other government programs, and employers determine how much to pay pharmacies and doctors to reimburse them for drugs that are dispensed to patients by using formulas based on the AWP for individual drugs. Source.
A jury in Montgomery County Circuit Court returned a verdict in favor of the State of Alabama in a case involving AWP and allegations of fraud, finding defendants GlaxoSmithKline and Novartis Pharmaceuticals Corp. liable for a total of $114,247,233, of which $80,989,539 is from GlaxoSmithKline and $33,257,694 is from Novartis.
For more on Tom's Firm's victory for the State of Alabama, go here.
FDA: Avastin Useless against Breast Cancer
News from this week ...
Avastin: A metastatic colorectal cancer treatment and advanced non-small cell lung cancer treatment.
In a past clinical trial sponsored by the National Cancer Institute, researchers gave breast cancer patients either Avastin and the breast cancer drug paclitaxel (also marketed as Taxol) or just paclitaxel alone.
The results showed that the drug combination of Avastin and Taxol almost doubled the time before breast tumors worsened, from just less than six months with paclitaxel alone to 11.3 months with the combination. Preliminary results of the study were released in April 2005, before the end of the study. Source: Here.
In combination with another drug, Avastin posed problems as well. Researchers in February 2006 abruptly halted recruitment of patients for a study combining the anti-cancer drugs Avastin and Xelox after several patients involved in the clinical testing died. Xeloda, a medication used alone since 1998 as a first-line defense in the treatment of colon cancer.
Avastin: A metastatic colorectal cancer treatment and advanced non-small cell lung cancer treatment.
In a past clinical trial sponsored by the National Cancer Institute, researchers gave breast cancer patients either Avastin and the breast cancer drug paclitaxel (also marketed as Taxol) or just paclitaxel alone.
The results showed that the drug combination of Avastin and Taxol almost doubled the time before breast tumors worsened, from just less than six months with paclitaxel alone to 11.3 months with the combination. Preliminary results of the study were released in April 2005, before the end of the study. Source: Here.
In combination with another drug, Avastin posed problems as well. Researchers in February 2006 abruptly halted recruitment of patients for a study combining the anti-cancer drugs Avastin and Xelox after several patients involved in the clinical testing died. Xeloda, a medication used alone since 1998 as a first-line defense in the treatment of colon cancer.
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