Drug Injury Watch

Will FDA Restrict Use Of Ketek And Put Increased "Black Box" Warning On Sanofi-Aventis Antibiotic?

FDA Advisory Panel: Ketek Side Effects Risks Outweigh Benefits For Bronchitis And Sinusitis; Urges Patient Medication Guide When Used For Pneumonia

In mid-December 2006, after two days of hearings, an FDA advisory panel recommended that the antibiotic Ketek should not be used as treatment for acute bacterial exacerbation of chronic bronchitis nor acute bacterial sinusitis.  The same FDA panel, which included drug-safety experts and infectious-disease specialists, voted in favor of allowing Ketek to continue to be prescribed for community-acquired pneumonia, a more serious medical condition.

According to a December 16, 2006 article in The Wall Street Journal (WSJ) by Anna Wilde Mathews:

Several committee members said they worried that Ketek's use in the milder conditions wasn't justified. "The risk of the drug seems to me to make it not appropriate to keep on using" for those infections, said Carl Norden, a professor at the University of Medicine and Dentistry of New Jersey.

Furthermore, as regards Ketek remaining on the market, a majority of this advisory panel recommended that there be two conditions.  First, the addition of a so-called "black box" warning to the Ketek package insert, or label, addressing the serious side effects which have been associated with Ketek use in the past.  Second, the panel members recommended that Sanofi-Aventis develop a medication guide for patients prescribed Ketek in the future.

It is important understand that the recommendations made by this advisory panel are "nonbinding", i.e., the FDA is not required to follow this panel's guidance as regards the future prescribing and use of Ketek.  If, however, the FDA does adopt all of the Ketek advisory panel's recommendations -- namely, (a) withdraw approval of Ketek for bronchitis and sinusitis, (b) mandate a "black box" warning for Ketek regarding serious side effects such as liver damage and liver failure, and (c) require distribution of a patient medication guide with future Ketek prescriptions -- one must wonder whether Sanofi-Aventis will continue to market Ketek in the U.S.

As Andrew Bridges reported in a December 15, 2006 Associated Press article: "Doctors have prescribed the antibiotic more than 5.6 million times in the United States since the FDA approved it in 2004."  And from the December 16 WSJ article:  "Last year Ketek was prescribed 3.35 million times in the U.S. and brought in $193 million, according to IMS Health."

To be clear, the FDA advisory panel did not recommend a Ketek recall for safety reasons.  But if the FDA fully adopts their recommendations, Ketek sales may be greatly diminished going forward.  In turn, Sanofi-Aventis could follow the lead of another drug company when it experienced increasing scrutiny about the safety of its antibiotic.  Earlier in 2006, Bristol-Myers Squibb (BMS) announced that it would stop marketing Tequin in the U.S. for "business" reasons -- a move which was very similar to the method that was used by BMS during its withdrawal of their anti-depressant drug Serzone in 2004.

Moreover, the likelihood of there being a "soft" recall of Ketek is increased by the ongoing Congressional investigations being led by Senator Charles Grassley.  According to a December 13, 2006 report by CBS News, "there is a new Congressional probe under way to determine whether Ketek should remain on the market." 

The online version of this December 13 CBS report about Ketek includes a link for an extended interview with one patient, Chuck Gregg, who suffered liver failure in early 2006 after he took samples of Ketek for bronchitis.  This CBS interview with Mr. Gregg and his wife makes a compelling case for why we should be concerned if the FDA does not act so as to adopt all of this advisory panel's recommendations regarding Ketek use in the U.S.

(Posted by: Tom Lamb)

Drug-induced Osteonecrosis Of The Jaw (ONJ) Caused By Bisphosphonates: Part Two

What Patients Should Know About The Signs And Symptoms As Well As Diagnosis Staging

As reported previously, there is increasing attention being paid to the association between the use of oral bisphosphonates such as Fosamax and osteonecrosis of the jaw (ONJ), a serious side effect which is also called jaw bone decay or jaw death. 

In part one of this series, sub-titled "What Are The Current Causation Theories And Which Patients Are At An Increased Risk", we considered two recent medical journal articles that provide information about how osteonecrosis of the jaw (ONJ) may be caused by Fosamax and other bisphosphonates as well as identify some of the predisposing, or risk, factors for developing ONJ.

Those same two medical journal articles give some important information about the early signs and symptoms of osteonecrosis of the jaw (ONJ) as well as the extent, or staging, of ONJ upon diagnosis.

To begin, we take a concise description of ONJ caused by bisphosphonates from an article published in the November 30, 2006 edition of The New England Journal of Medicine (NEJM) called "Osteonecrosis of the Jaw -- Do Bisphosphonates Pose a Risk?", by Dr. John P. Bilezikian:

Osteonecrosis of the jaw is characterized clinically by an area of exposed bone in the mandible, maxilla, or palate that typically heals poorly or does not heal over a period of 6 to 8 weeks....

The lesion is painful in many, but not all, patients, and infection is often present. Approximately two thirds of cases involve the mandible and the rest involve the maxilla.

For some discussion about the early signs and symptoms of ONJ we turn to an article published in Hematology 2006 called "Bisphosphonate Complications Including Osteonecrosis of the Jaw":

Typical presentation is in the form of a nonhealing extraction socket, presence of exposed bone, gingival swelling or purulent discharge, when local debridement and antibiotics are ineffective. Often, a nonhealing ulcer or exposed bone may be detected on routine oral care that may remain asymptomatic, until superinfection sets in when swelling, pain, loosening of teeth and discharge may develop. Occasionally, pain in the jaw bone may be the only symptom without any evidence of radiological abnormalities. Eighty percent of patients report an antecedent dental procedure prior to presentation. Median age in one series was 68 years, mandible as the site of involvement is seen in two-thirds of the patients and maxillary involvement is in a third.

This same article about osteonecrosis of the jaw (ONJ) in Hematology 2006 also sets forth a basic explanation about the extent, or staging, of this condition upon diagnosis:

Oral surgical colleagues have reported a staging system from I to III based on the presence of symptoms such as pain, degree of swelling, ulceration, exposure of bone, response to topical antibiotic rinses, requirement for debridement and requirement of intravenous antibiotics....

Staging ONJ appropriately based on clinical and radiographic findings may be used to direct specific local and systemic therapy. Stage I disease as characterized by asymptomatic detection of exposed bone without soft tissue infection, may be managed conservatively with a non-surgical conservative approach to avoid further osseous injury....  Stage II disease characterized by presence of symptoms around the area of exposed bone secondary to soft tissue swelling and/or bone infection may require culture-directed long-term and maintenance antimicrobial therapy, analgesic management, in addition to conservative measures outlined for stage I disease....  Stage III disease is characterized by the presence of a pathological fracture (not related to metastatic disease), exposed bone associated with soft tissue infection, which is not manageable with antibiotics alone due to the volume of necrotic bone.

Although dentists and oral surgeons are becoming more aware of the association between oral bisphosphonates such as Fosamax and osteonecrosis of the jaw (ONJ), patients using these drugs should be knowledgeable about the symptoms of this serious side effect and what treatment is appropriate for them if they are, unfortunately, diagnosed with ONJ.

(Posted by: Tom Lamb)

Drug-induced Osteonecrosis Of The Jaw (ONJ) Caused By Bisphosphonates: Part One

What Are The Current Causation Theories And Which Patients Are At An Increased Risk

As reported previously, there is increasing attention being paid to the association between the use of oral bisphosphonates and osteonecrosis of the jaw (ONJ), the serious side effect which is commonly called jawbone death, bone decay, or jaw rot. 

Two recent medical journal articles provide information about how osteonecrosis of the jaw (ONJ) may be caused by Fosamax and other bisphosphonates as well as identify some of the predisposing, or risk, factors for developing ONJ.

We start with an article called "Osteonecrosis of the Jaw -- Do Bisphosphonates Pose a Risk?", published in the November 30, 2006 edition of The New England Journal of Medicine (NEJM), where Dr. John P. Bilezikian offers this on causation:

If there is a relationship between bisphosphonates and osteonecrosis of the jaw, what might explain it? The jaw is often subject to spontaneous, local trauma as well as trauma caused by dental procedures. The mucosa of the mouth is very thin and may therefore permit unroofing of the alveolar bone immediately beneath it when trauma or infection occurs. As potent inhibitors of osteoclast activity, the nitrogen-containing bisphosphonates might retard skeletal repair processes associated with trauma to or infection of the oral mucosa that involves the underlying bone. Since the jawbones are in constant use and are characterized by active remodeling, bisphosphonates might accumulate there preferentially, resulting in concentrations that exceed those found elsewhere in the skeleton. Other potential mechanisms include the possible antiangiogenic effects of nitrogen-containing bisphosphonates and the effects of these agents on T-cell function.

As for the ONJ risk factors, Dr. Bilezikian states: "Predisposing factors for the development of osteonecrosis of the jaw appear to be dental disease, dental surgery (e.g., tooth extraction), oral trauma, periodontitis, and poor dental hygiene."

Further discussion about how bisphosphonates such as Fosamax causes ONJ and when that side effect is more likely to develop can be found in the article by Dr. Bhoomi Mehrotra and Dr. Salvatore Ruggiero called "Bisphosphonate Complications Including Osteonecrosis of the Jaw", published in Hematology 2006:

The mechanism of bisphosphonates-induced osteonecrosis is unclear. However, several predisposing factors have been identified. Periodontal disease, dentoalveolar surgery, prior trauma, corticosteroid therapy, immune-compromised state predisposing to increased risk of infection, possible vascular insufficiency and an underlying hypercoagulable state secondary to underlying malignancy have been implicated as possible etiologic or precipitating factors.... The unique predisposition for bony necrosis in the jaw may be related to the microenvironment in the maxilla and mandible secondary to compromised vascular supply and presence of oral microflora that may super-infect a poorly healing wound in the jaw bone. In addition, the constant microtrauma from jaw movement and lack of adequate bone remodeling in the presence of bisphosphonates may contribute to the genesis of osteonecrosis of the jaw (ONJ). Although spontaneous osteonecrosis is reported in a minority of cases, the majority of patients give a history of some prior dental or oral surgical manipulation.  Several investigators have identified increasing duration of exposure, type of bisphosphonate, older age and prior history of a dental procedure as risk factors for the development of ONJ....

According to Dr. Bilezikian's November 2006 NEJM article: "Approximately two thirds of cases involve the mandible and the rest involve the maxilla."

In part two of this series, sub-titled "What Patients Should Know About The Signs And Symptoms As Well As Diagnostic Staging", we get from these same two medical journal articles some important information about the early signs and symptoms of osteonecrosis of the jaw (ONJ) as well as the extent, or staging, of ONJ upon diagnosis.

(Posted by: Tom Lamb)

New Birth Control Patch Warnings In Canada About Being Overweight, Sauna Or Whirlpool Heat

No Similar Changes To Ortho Evra Label In U.S. As Of Early December 2006

On November 23, 2006 Health Canada released a drug safety alert -- which consisted of a so-called "Dear Doctor" letter and a public advisory for patients -- about the norelgestromin and ethinyl estradiol transdermal system, better known as the birth control patch or, more simply, "the patch".

Although this announcement by Janssen-Ortho Inc., in consultation with Health Canada, focused on new safety information pertaining to its product Evra, the birth control patch that is marketed in Canada, their alert seems to be equally applicable to the Ortho Evra patch sold in the U.S.

The EVRA* transdermal system marketed in Canada contains 6.0 mg norelgestromin (NGMN) and 0.60 mg ethinyl estradiol (EE) and is approved for use in contraception (prevention of pregnancy). ORTHO EVRA® is the formulation of EVRA* marketed in the United States and contains 6.0 mg NGMN and 0.75mg EE. Although EVRA* and ORTHO EVRA® are manufactured differently and therefore contain different total amounts of estrogen, the risk of side effects reported for ORTHO EVRA® is considered to apply equally to the EVRA* formulation available in Canada.

This birth control patch warning in Canada started by addressing the situation which arose in September 2006 when we learned about two conflicting studies about Ortho Evra concerning whether there is any connection between Ortho Evra and serious blood clot side effects. 

The results of a recent study indicate that women using the ORTHO EVRA contraceptive patch (the formulation of EVRA marketed in the United States) had an increased risk of blood clots in the legs and lungs compared to women using an oral contraceptive. Another study indicated no difference in the risk of blood clots in the legs and lungs in women using ORTHO EVRA compared to women using an oral contraceptive.

Next, there are two new safety warnings about the Evra birth control patch set forth in this November 2006 Health Canada safety alert.

• "Women who are obese are at particularly high risk of blood clots."
• "Due to a theoretical risk of unintentional increase in estrogen exposure from the patch, patients are recommended not to expose the patch area to sources of heat such as sauna or whirlpool bath."

As of December 3, 2006, however, no corresponding warning about being overweight nor the sauna and whirlpool heat exposure had been issued by Ortho-McNeil Pharmaceutical -- a Johnson & Johnson (J&J) company -- for their Ortho Evra product in the U.S.  It is not clear at present whether J&J intends to revise the package insert, or label, for Ortho Evra to warn women that they are perhaps at an increased of developing serious blood clots if they are overweight or if the birth control patch is exposed to certain heated environments such as saunas and whirlpools.

Further comparing conduct in Canada and the U.S., in September 2006 J&J and the FDA did announce that the conflicting recent studies had caused a renewed concern about the association between Ortho Evra and certain blood clot disorders like pulmonary embolisms and deep vein thrombosis (DVT).  J&J did not, however, issue any Dear Doctor letter to U.S. health care providers then, nor have they done so since September.  One must wonder, why the difference?

(Posted by: Tom Lamb)