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?
