Fosamax associated with unusual fractures of the thigh bone

In the latest research to cast a shadow on the safety of a popular bone-strengthening medication, researchers report that long-term use of Fosamax is associated with unusual fractures of the thigh bone.

The fractures were low-energy fractures, meaning that they all occurred from a fall from standing height or less, and the bone cracks were in an unusual horizontal pattern. About one-third of women with these types of fractures were on long-term therapy to prevent osteoporosis, the researchers noted. Of these women, two-thirds were taking Fosamax (alendronate), for an average of more than seven years.

Fosamax is a bisphosphonate, a class of drugs used to increase bone mass and reduce the risk of fracture in those who have osteoporosis.

“These were peculiar fractures that would occur when the women were basically doing nothing,” said the study’s senior author, Dr. Joseph Lane, chief of metabolic bone disease at the Hospital for Special Surgery at Weill Cornell Medical College in New York City.

Fifteen women were included in Lane’s analysis. The average time on Fosamax was 5.4 years before they experienced the unusual femur fracture. Of these 15, 10 women had similar, atypical fractures. These women had been taking Fosamax for an average of 7.3 years, while the remaining five had only been on the drug for an average of 2.8 years.

“Our results provide further evidence of a potential link between alendronate use and low-energy fractures of the femur,” the authors said in a letter reporting their findings, which is published in the March 20 issue of the New England Journal of Medicine. But, the authors acknowledge the limitations of their retrospective analysis and suggest that these findings need to be confirmed in a prospective study.

Lane said there are several theories as to how alendronate could be related to these fractures. One is that the drug slows down the development of new collagen, and he said new collagen is very strong. Another could be because there is slower bone turnover on the medications. That could mean there may be accumulated microdamage in the bone, making it more susceptible to fracture in certain women.

Lane said that women taking this medication should keep taking it, and these findings shouldn’t cause them alarm. “This is a great drug that does wonderful things. Bisphosphonates have dropped the rate of hip fractures,” he added.

Ron Rogers, a spokesman for Merck, which manufactures Fosamax, said, “Fosamax has not been associated with an increased risk of fracture at any skeletal site.” Rogers also noted that this study didn’t prove a cause and effect relationship between the drug and these unusual fractures, and that the researchers noted that 63 percent of women treated for low-energy fractures weren’t taking bisphosphonates at all.

Dr. Loren Wissner Greene, co-director of the osteoporosis and metabolic bone disease program at the New York University School of Medicine, agreed that this study has just pointed out an association between Fosamax use and these fractures, not proven a causal relationship.

Still, Greene said she believes these atypical breaks probably are related to the medication, although she added, “If this is a related complication, it appears to be very rare.”

Like Lane, she said, “Alendronate is still a very valuable drug in decreasing the risk of hip fracture.” But, she said, what would be helpful is a test that could identify who is in the sub-population that might have a problem on this medication.

Lane said that women who’ve been taking this medication for a long time and have test results that suggest low bone turnover, may want to take a “bone holiday,” and stop taking the medication for a year. But, he added, this shouldn’t be done on your own. “If you’ve been on alendronate for a long time, talk to your doctor,” he suggested.

The U.S. Food and Drug Administration in January issued an alert to physicians about the possibility of severe bone pain occurring as a result of bisphosphonate therapy. Additionally, last year Fosamax was also implicated in some cases of atrial fibrillation — a serious type of irregular heartbeat — though the FDA hasn’t found evidence to support this association.

Fosamax

Generic Name: alendronate

What is the most important information I should know about Fosamax?

Do not take an Fosamax tablet if you cannot sit upright or stand for at least 30 minutes. Fosamax can cause serious problems in the stomach or esophagus (the tube that connects your mouth and stomach). You will need to stay upright for at least 30 minutes after taking this medication.

Take the Fosamax tablet first thing in the morning, at least 30 minutes before you eat or drink anything or take any other medicine.
Take each dose with a full glass (6 to 8 ounces) of water. Use only plain water (not mineral water) when taking an Fosamax tablet.

For at least the first 30 minutes after taking an Fosamax tablet, do not lie down or recline; do not eat or drink anything other than plain water; and do not take any other medicines including vitamins, calcium, or antacids.

Some people using medicines similar to Fosamax have developed bone loss in the jaw, also called osteonecrosis of the jaw. Symptoms of this condition may include jaw pain, swelling, numbness, loose teeth, gum infection, or slow healing after injury or surgery involving the gums. You may be more likely to develop osteonecrosis of the jaw if you have cancer or have been treated with chemotherapy, radiation, or steroids. Other conditions associated with osteonecrosis of the jaw include blood clotting disorders, anemia (low red blood cells), and a pre-existing dental problem.

Fosamax is only part of a complete program of treatment that may also include diet changes, exercise, and taking calcium and vitamin supplements. Follow your diet, medication, and exercise routines very closely.

What is Fosamax?

Fosamax is in the group of medicines called bisphosphonates (bis FOS fo nayts). It alters the cycle of bone formation and breakdown in the body. Fosamax slows bone loss while increasing bone mass, which may prevent bone fractures.

Fosamax is used to treat or prevent postmenopausal osteoporosis and steroid-induced osteoporosis. Fosamax is also used to treat Pagets disease of bone.

Fosamax may also be used for purposes other than those listed in this medication guide.

What should I avoid while taking Fosamax?

Do not take any other medicines including vitamins, calcium, or antacids for at least 30 minutes after taking an Fosamax tablet. Do not lie down for at least 30 minutes after you take an Fosamax tablet.
What are the possible side effects of Fosamax?
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat. Stop using Fosamax and call your doctor at once if you have any of these serious side effects:

• chest pain;
• difficulty or pain when swallowing;
• pain or burning under the ribs or in the back;
• new or worsening heartburn;
• severe joint, bone, or muscle pain; or
• jaw pain, numbness, or swelling.

Continue using Fosamax and talk with your doctor if you have any of these less serious side effects:

• mild heartburn or stomach upset;
• diarrhea, gas, or constipation;
• joint pain or swelling;
• swelling in your hands or feet;
• back pain; or
• dizziness, weakness, or headache.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome.

What other drugs will affect Fosamax?

Antacids, supplements, or medicines that contain aluminum, calcium, magnesium, or other minerals can interfere with how your body absorbs Fosamax. If you use these other medicines, do not that take them for at least 30 minutes after taking an Fosamax tablet.

Before using Fosamax, tell your doctor if you also use aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) such as celecoxib (Celebrex), diclofenac (Voltaren), diflunisal (Dolobid), ibuprofen (Motrin, Advil), indomethacin, ketoprofen (Orudis), ketorolac (Toradol), naproxen (Aleve, Naprosyn), piroxicam (Feldene), and others.

There may be other drugs that can affect Fosamax. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Tyverb is back in Europe

The European Commission has referred GlaxoSmithKline Plc’s breast cancer treatment Tyverb back for a fresh assessment by drugs regulators following new data from Europe’s biggest pharmaceuticals company.

Glaxo said on Tuesday that Tyverb, which is already on sale in the United States under the name Tykerb, had been referred back to the EU’s Committee for Medicinal Products for Human Use (CHMP) for further discussion.

It said the new information was from a standard pharmacovigilance review of clinical trial and post-marketing data.

Glaxo’s Tyverb Referred for More Discussion in Europe

GlaxoSmithKline Plc’s Tyverb breast cancer drug was sent back to a European regulatory panel after new data showed the medicine may raise the risk of liver damage, slowing final approval.

The European Commission returned the application to the region’s health-care regulator for further discussion, probably during its April 21-24 meeting, London-based Glaxo said today in an e-mailed statement. An agency committee recommended approval of Tyverb following a review in December.

Tyverb is one of the medicines Glaxo is relying on to help counter slowing growth in sales of its top-selling asthma drug Advair and diabetes pill Avandia and the loss of patent protection on other products. The commission was expected to issue a final decision on the breast cancer drug between Feb. 22 and March 8, Glaxo said.

“It’s not particularly good news,” analyst Nick Turner of Mirabaud Securities in London said in a telephone interview. “This is a drug that promised much but isn’t likely to deliver.”

The new data showed signs that the medicine can raise the level of liver enzymes in patients, a possible warning sign for damage to the organ. Elevated liver enzymes were seen in four out of 1,000 patients, and “generally returned to normal” after they stopped using the drug, according to the U.K. company.

Positive Profile

“GSK believes these data do not change the positive benefit-risk profile for Tyverb in the proposed indication,” Glaxo said in the statement.

Glaxo shares rose 38 pence, or 3.7 percent, to close at 1,054 pence in London trading.

The European Medicines Agency said in December that it recommended conditional approval of Tyverb for breast cancer that has advanced or spread to other parts of the body in patients with the HER-2 gene, which makes the disease more aggressive. Conditional approval is valid for one year while the company obtains more information about the medicine and its effectiveness, EMEA said at the time.

Heparin being tested again

U.S. health officials have ordered all imports of the blood thinner heparin, and its raw ingredient, stopped at the border for testing to detect a contaminant linked to 19 deaths.

The Food and Drug Administration announced the move Friday, the latest step in its widening investigation of hundreds of allergic-type reactions linked to Baxter International’s heparin injections.

The FDA found the contaminant in 20 of 28 samples of raw heparin that the agency tested from Baxter’s main supplier, a Chinese factory owned by Wisconsin-based Scientific Protein Laboratories.

A different brand of heparin also has been recalled in Germany after 80 patients there got sick, and the German manufacturer said Friday that it was narrowing down the source of contamination to another Chinese supplier.

FDA announced some good news Friday, saying it had learned of no additional deaths and just two more allergic reactions since Baxter recalled the last of the suspect heparin late last month.

Scientists don’t yet know exactly what the contaminant is, except that it mimics heparin so closely that standard drug-purity tests won’t catch it. Nor is it certain that the contaminant is to blame for the allergic reactions, although it is the prime suspect.

But the FDA is “very close” to identifying the substance, a step that should help tell if the contaminant got into heparin by accident or by fraud, said FDA drug chief Dr. Janet Woodcock.

Heparin is derived from pig intestines, and China is the world’s leading supplier. Tiny family-run workshops near slaughterhouses send batches of raw ingredients to larger middlemen before they reach factories like SPL’s in Changzhou. The FDA hasn’t yet inspected those workshops, saying that was something under discussion with Chinese officials.

Two weeks ago, the FDA urged all remaining U.S. heparin manufacturers to start using more sophisticated tests to be sure their products were contaminant-free. Friday, the agency said worldwide testing had begun.

The added hurdle for imports “will improve our safety net,” Woodcock said. “We will get a much better picture of whether there’s any contaminant existing, and we can trace it back” to its source.

Most of the actual import testing will be done by five of the nation’s leading heparin manufacturers, which will be cleared to sell their products once the FDA receives those test results.

The FDA itself will test any remaining shipments that arrive from abroad.

The FDA wouldn’t name the five companies that will do their own testing, and acknowledged it has no plans to do spot checks of the quality of those companies’ tests.

Herapin recalled by Japanese firms

Three Japanese firms recalled the active ingredient in the blood thinner herapin as a “precaution” over concerns of ties to Chinese factories, officials said.

The U.S. Food and Drug Administration announced that three unnamed Japanese firms recalled the active ingredient in herapin manufactured by Scientific Protein Laboratories based in Wisconsin.

At least four people died from allergic reactions to the drug and hundreds suffered life-threatening reactions in the United States and Germany, though none of these reactions stem from products manufactured at Scientific Protein, the Chicago Tribune reported Tuesday.

“The three Japanese companies made clear that the recall was simply a precaution, as there has not been a pattern of adverse reactions to heparin reported in Japan similar to what has been observed in the U.S. and Germany,” Scientific Protein said in a statement Monday.

FDA officials said it found “herapin-like” substances in recalled batches of herapin sold by Baxter International Inc. linked to production facilities in rural China.

The supply chain for herapin production begins in unregulated family-owned pig farms in rural China before reaching Scientific Protein’s Chinese facilities.

Complications of Heparin Therapy

Heparin comes in many forms and is commonly used in cancer patients. Since its discovery in 1923, heparin has been the primary parenteral anticoagulant used worldwide for the prevention and treatment of blood clots and for maintaining patency of catheters. The most frequent side effect of heparin therapy is bleeding. However, a less common but potentially devastating complication of heparin exposure, immune-mediated heparin-induced thrombocytopenia (HIT), is now well described. Paradoxically, immune-mediated HIT is associated with the development of new thrombosis or worsening of preexisting thromboses rather than bleeding.

A mild decline in the platelet count occurs commonly in patients receiving heparin and is most often non-immune mediated. This generally occurs within 5 days after institution of the drug and is not associated with thrombosis. Heparin can be safely continued and the platelet count generally returns to normal within a few days.

Immune-mediated HIT, on the other hand, is characterized by a more significant decline in platelets defined as either a drop in the platelet count to under 150,000 or greater than 50% decline in the platelet count following the initiation of heparin therapy. It typically develops after 4-10 days of heparin therapy but can suddenly occur within 24 hours of heparin exposure if the patient has been sensitized to heparin within the preceding three months. For these reasons, all patients receiving heparin should have their platelet count monitored.

The frequency of HIT may be as high as 3% in patients treated with heparin for at least 4 days. The likelihood that HIT will develop depends upon the source and dose of heparin. Therapeutic doses of heparin are more likely than prophylactic doses to cause HIT and it is most common with unfractionated heparin. In fact, HIT has only rarely been associated with low molecular weight heparin.

HIT is caused by antibodies directed against an antigen complex that is composed of heparin and platelet factor 4. This antibody-antigen complex binds to the surface of platelets resulting in platelet activation and aggregation. It also indirectly leads to the generation of thrombin, further promoting the onset or extension of thrombosis through activation of the coagulation cascade.

In patients who develop HIT, an alarming 50-60% will develop thrombotic complications within 30 days following the diagnosis without further therapy. Venous thromboses are far more likely than arterial thromboses.

Serologic testing should be ordered to confirm the clinical suspicion. However, the results typically are not available for several days, making HIT a clinical diagnosis initially. Indeed, if one waits for the results of the confirmatory tests to act, it may be too late to prevent or effectively treat thrombosis. Laboratory tests include functional assays (serotonin release assay, heparin-induced platelet activation) and an antigenic assay (ELISA). When the functional and antigenic assays are combined both sensitivity and specificity exceeds 90%.

Blockbuster anemia drugs may lead to death

Drug maker Amgen Inc. said Friday it expanded black box warnings about risks of death and tumor growth of its blockbuster anemia drugs.

The warnings approved by the Food and Drug Administration state that the company’s drugs increased death and accelerated tumor growth in patients with early stage breast cancer and cervical cancer. Earlier labeling warned of similar risks in other types of cancer.

The changes apply to Thousand Oaks, Calif.-based Amgen’s Aranesp and Epogen, as well as Johnson & Johnson’s Procrit. The drugs treat the blood-disorder anemia in patients with kidney failure and those on chemotherapy. Amgen manufacturers all three, though New Brunswick, N.J.-based J & J sells Procrit.

The language states that the problems occurred when doctors treated patients with elevated levels of the drugs, which increase red blood cell levels.

The action came less than a week before a meeting where government advisers are scheduled to review the risks of the blockbuster medications.

Since FDA began scrutinizing the drugs last March, shares of Amgen have sunk 27 percent. U.S. sales of its anemia treatments fell more than 10 percent to $6.3 billion for the year.

Wall Street analysts expect sales to fall further in 2008 following next week’s review by FDA’s cancer experts. The panel could recommend halting use of the drugs for certain types of cancers, or in all cancer patients. Recommendations will not apply to Amgen’s Epogen, which is used almost exclusively by kidney failure patients on dialysis.

If FDA removes only some cancer indications, Amgen’s anemia drug sales could lose between $150 million to $250 million for 2008, according to estimates by Goldman Sachs’ analyst May-Kin Ho.

FDA twice updated anemia drug labels last year, most recently in November. Amgen disclosed new data in December on the drugs’ risks in early stage breast cancer and cervical cancer patients, sending shares downward nearly 20 percent. The new label incorporates detail from those studies.

Bear Stearns analyst Mark Schoenebaum said the effect of Friday’s changes would be minimal for Amgen, since cervical cancer accounts for about 1 percent of the Aranesp market. He also noted that the previous label already highlighted the breast cancer risks.

But Stanford Group Co. analyst Gregory Frykman said the new warnings could attract tougher regulations from Medicare, the government’s health plan for seniors. Last summer Medicare ruled that it would only pay doctors to administer anemia drugs if they were prescribed at low levels.

Frykman said the new warnings could convince Medicare to scale back its policy again, perhaps only paying for the drugs when used in certain types of cancer.

Wall Street reacted positively to the news, sending shares up 1.02 cents, or 2.3 percent, to $45.20 in after-hours trading. Shares fell 14 cents to close at $44.18 in regular trading.

Reference Material on Anemia

Anemia, condition in which the concentration of hemoglobin in the circulating blood is below normal. Such a condition is caused by a deficient number of erythrocytes (red blood cells), an abnormally low level of hemoglobin in the individual cells, or both these conditions simultaneously. Regardless of the cause, all types of anemia cause similar signs and symptoms because of the blood’s reduced capacity to carry oxygen. These symptoms include pallor of the skin and mucous membranes, weakness, dizziness, easy fatigability, and drowsiness. Severe cases show difficulty in breathing, heart abnormalities, and digestive complaints.

One of the most common anemias, iron-deficiency anemia, is caused by insufficient iron, an element essential for the formation of hemoglobin in the erythrocytes. In most adults (except pregnant women) the cause is chronic blood loss rather than insufficient iron in the diet, and, therefore, the treatment includes locating the source of abnormal bleeding in addition to the administration of iron.

Pernicious anemia causes an increased production of erythrocytes that are structurally abnormal and have attenuated life spans. This condition rarely occurs before age 35 and is inherited, being more prevalent among persons of Scandinavian, Irish, and English extraction. It is caused by the inability of the body to absorb vitamin B12 (which is essential for the maturation of erythrocytes).

There are several conditions that cause the destruction of erythrocytes, thereby producing anemia. Allergic-type reactions to bacterial toxins and various chemical agents, among them sulfonamides and benzene, can cause hemolysis, which requires emergency treatment. In addition, there are unusual situations in which the body produces antibodies against its own erythrocytes; the mechanism triggering such reactions remains obscure.

A year ago:

FDA issues new warnings on widely used anemia drugs

Federal health officials have issued stern new warnings for doctors to more carefully prescribe widely used anemia drugs that can increase the risk of death and other serious problems in patients with cancer and kidney disease.