Myocardial Infarction Risk Increases After Joint Replacement .


The risk for acute myocardial infarction increases in the weeks following total hip or total knee replacement, according to an Archives of Internal Medicine study. A commentator stresses the need for perioperative vigilance with all surgery.

Using Danish national health databases, researchers compared risks in nearly 100,000 patients undergoing joint replacement with those in matched controls not undergoing surgery. Hip replacement carried a 25-fold increased risk for MI relative to controls in the first 2 weeks after surgery, returning to background values after 6 weeks. For knee replacement, the risk was 30-fold higher by 2 weeks, and then dropped rapidly.

A commentator urges physicians to “actively work to reduce perioperative risk.”

Source: Archives of Internal Medicine

Young People Who Use Tanning Beds Face Higher Melanoma Risk.


People who start using tanning beds before the age of 35 face almost double the risk for melanoma, compared with people who never used tanning beds, according to a meta-analysis in BMJ.

Researchers looked at 27 case-control and cohort studies examining sunbed use and melanoma; the studies comprised roughly 11,500 cases of melanoma. Overall, they found that people who had reported ever using a tanning bed were more likely to have melanoma than people who never used a tanning bed (relative risk, 1.20). People who started before the age of 35 were at even greater risk (RR, 1.87). The authors estimate that nearly 3500 cases of melanoma in Europe — about 5% of the total cases there — are attributable to sunbed use annually.

Source: BMJ

 

Policy Roundup: Doctor Shortage, Medicaid and Mortality, Availability of Generics.


Health policy questions are coming into sharper focus in the weeks following the Supreme Court’s ruling on the Affordable Care Act (ACA).

One issue: With the expansion of coverage in the U.S., are there enough physicians to care for the new arrivals into the system? According to a New York Times story, the answer is no. Nationally, the Times reports, even without the ACA, there would be a shortage of over 100,000 physicians by 2025.

Another issue: Would the ACA’s proposed Medicaid expansion improve health outcomes? A study in the New England Journal of Medicine shows that expansion in three states during the early 2000s significantly improved mortality rates, relative to neighboring states that did not expand coverage. Improvements were most striking among the nonwhite, the aging, and the poor.

Finally: Agreements under which major drug companies pay makers of generic products to keep generics off the market were considered to be “unreasonable restraint of trade” by a federal appeals court in Philadelphia, according to the New York Times. The Supreme Court is likely to get the case, the Times reports.

Source: New York Times story on physician shortage / NEJM article.

FDA Approves Three New Treatments .


The FDA approved new treatments for several conditions last week, including:

  • Chronic obstructive pulmonary disease: Aclidinium bromide (marketed as Tudorza Pressair) is a new long-acting antimuscarinic agent, given twice daily as a dry powder inhaler, for the long-term maintenance treatment of bronchospasm in COPD patients.
  • Severe hypertriglyceridemia: A new omega-3 pill containing icosapent ethyl (Vascepa) may be used in addition to dietary changes to reduce triglycerides in adults whose levels reach 500 mg/dL or greater.
  • Advanced breast cancer: Everolimus (Afinitor), previously approved for advanced renal cancer and other conditions, is now indicated for use with exemestane to treat postmenopausal women with hormone receptor–positive, HER2-negative breast cancer whose illness has recurred or progressed after receiving letrozole or anastrozole.

Source: Physican first Watch.

Novartis drug Afinitor® approved by European Commission to treat patients with the most common form of advanced breast cancer.


The European Commission has approved Afinitor® (everolimus) tablets* for the treatment of hormone receptor-positive (HR+), HER2/neu-negative (HER2-) advanced breast cancer (HR+ advanced breast cancer), in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor[1].
“The approval of Afinitor is an important milestone marking the first major advance for women in the European Union with hormone receptor-positive advanced breast cancer since the introduction of aromatase inhibitors more than 15 years ago,” said Hervé Hoppenot, President, Novartis Oncology. “Treatment with Afinitor gives women a new option in the battle against this advanced form of breast cancer, where there remains a significant unmet need.”

 

The approval was based on the Phase III BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) trial[1]. The randomized, double-blind, placebo-controlled, multi-center study of 724 patients found that treatment with Afinitor plus exemestane more than doubled median progression-free survival (PFS) to 7.8 months, compared to 3.2 months with exemestane alone (hazard ratio=0.45 [95% Cl: 0.38 to 0.54]; p<0.0001), by local investigator assessment[3]. An additional analysis based on an independent central radiology review showed Afinitor extended median PFS to 11.0 months compared to 4.1 months (hazard ratio=0.38 [95% CI: 0.31 to 0.48]; p<0.0001)[3]. The most common grade 3-4 adverse reactions (incidence >= 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis and diarrhea[3].

 

“By boosting the effectiveness of endocrine therapy, Afinitor significantly extends the time women with hormone receptor-positive advanced breast cancer live without tumor progression,” said Jose Baselga, MD, PhD, Chief, Hematology/Oncology, Massachusetts General Hospital and co-lead investigator of the BOLERO-2 trial. “Afinitor, the first mTOR inhibitor to be approved for this disease, has the potential to redefine the way this common form of advanced breast cancer is treated.”

 

Each year, an estimated 220,000 women globally will be diagnosed with HR+ advanced breast cancer[1],[4]. For these women, endocrine therapy remains the cornerstone of treatment, but most will eventually develop resistance to therapy[5]. This therapeutic resistance has been associated with overactivation of the PI3K/AKT/mTOR pathway[5]. Afinitor works to target the mTOR pathway in cells. mTOR is a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism[5].

 

The European Commission decision follows the positive opinion adopted by the Committee for Medicinal Products for Human Use on June 21, 2012 for Afinitor for the treatment of HR+ advanced breast cancer and applies to all 27 EU member states, plus Iceland and Norway[6]. On July 20, 2012, the US Food and Drug Administration approved Afinitor in combination with exemestane in the HR+/HER2- population after failure of letrozole or anastrazole[7]. Additional regulatory submissions for Afinitor in advanced breast cancer are under way worldwide. Afinitor is also being studied in HER2-positive breast cancer in two ongoing Phase III trials.

 

About Advanced Breast Cancer

Advanced breast cancer is comprised of metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[8]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the bones or liver[8]. Locally advanced breast cancer occurs when the cancer has spread to lymph nodes and/or other tissue in the area of the breast, but not to distant sites in the body[8].

 

It is estimated that women with metastatic breast cancer have a life expectancy of approximately 18-36 months after diagnosis and median survival for women with stage III disease is less than five years[9],[10].

 

HR+ advanced breast cancer is characterized by hormone receptor-positive tumors, a group of cancers that express receptors for certain hormones such as estrogen and progesterone. Cancer cell growth can be driven by these hormones[8]. The presence of estrogen receptor (ER) and/or progesterone receptor (PgR) is one of the most important predictive and prognostic markers in human breast cancers, and is collectively referred to as hormone receptor-positive[8].

 

About Afinitor (everolimus)

Afinitor® (everolimus) is approved in the European Union for the treatment of hormone receptor-positive (HR+), HER2/neu-negative (HER2-) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole.

 

Afinitor (everolimus) tablets is approved in more than 80 countries including the United States and throughout the European Union in the oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy, and in the United States and European Union for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin.

 

Everolimus is also available from Novartis for use in non-oncology patient populations under the brand names Afinitor® or Votubia®, Certican® and Zortress® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

 

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

 

Afinitor® Important Safety Information

Afinitor®/Votubia® can cause serious side effects including lung or breathing problems, infections and renal failure, which can lead to death. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar and cholesterol levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed.

 

The most common adverse drug reactions (incidence >=15%) are mouth ulcers, diarrhea, feeling weak or tired, skin problems (such as rash or acne), infections, nausea, swelling of extremities or other parts of the body, loss of appetite, headache, inflammation of lung tissue, abnormal taste, nose bleeds, inflammation of the lining of the digestive system, weight decreased and vomiting. The most common grade 3-4 adverse drug reactions (incidence >=2%) are mouth ulcers, feeling tired, low white blood cells (a type of blood cell that fights infection), diarrhea, infections, inflammation of lung tissue, diabetes and amenorrhea. Cases of hepatitis B reactivation and blood clots in the lung and leg have been reported.

 

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as “potential,” “will,” “under way,” “being studied,” or similar expressions, or by express or implied discussions regarding potential new indications or labeling for everolimus or regarding potential future revenues from everolimus. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with everolimus to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that everolimus will be submitted or approved for any additional indications or labeling in any market or at any particular time. Nor can there be any guarantee that everolimus will achieve any particular levels of revenue in the future. In particular, management’s expectations regarding everolimus could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection; government, industry and general public pricing pressures; competition in general; unexpected manufacturing issues; the impact that the foregoing factors could have on the values attributed to the Novartis Group’s assets and liabilities as recorded in the Group’s consolidated balance sheet; and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

 

About Novartis

Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2011, the Group achieved net sales of USD 58.6 billion, while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 126,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

 

References

  1. Novartis Data on File.
  2. Redmond C. Breast Cancer Hormone Therapy Options. Available at: http://christine-redmond.suite101.com/breast-cancer-hormone-therapy-options-a197304. Accessed April 27, 2012.
  3. Piccart M et al. Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial. Abstract #559. American Society of Clinical Oncology 2012 Annual Meeting, Chicago, IL.
  4. Buckley N, Isherwood A, Breast Cancer. Decision Resources. 2011.
  5. Baselga J. Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer. New England Journal of Medicine. February 9, 2012.
  6. European Medicines Agency. Summary of Opinion for Afinitor. June 21, 2012.
  7. FDA Approval Announcement of Afinitor in Advanced HR+ Breast Cancer. July 20, 2012.
  8. National Cancer Institute. What You Need to Know About Advanced Breast Cancer. Available at: http://www.cancer.gov/cancertopics/wyntk/breast/WYNTK_breast.pdf. Accessed on March 8, 2012.
  9. Giordano S. Update on Locally Advanced Breast Cancer. The Oncologist, 2003.Buckley N, Isherwood A. Breast Cancer. Decision Resources, March 2011.
  10. Eniua A, Palmierib F and Perez E. Weekly Administration of Docetaxel and Paclitaxel in Metastatic or Advanced Breast Cancer. The Oncologist, 2005.

 

Source: Novartis News letter.

Loosening the Grip of Post-Stroke Spasticity.


 

 

Abstract

Physical therapy and medication can help relieve this sometimes painful and disabling condition

William and Tuye Collins are coming up on an anniversary—though it’s one they’d probably rather not have. On the evening of May 10, 2000, Tuye (pronounced TOO-yee) came home from a church gathering to find her husband sprawled on the bedroom floor. He had had a major stroke that severely impaired his ability to speak and swallow.

 

As if being paralyzed on the right side weren’t hard enough, his right arm and leg were bent and his right foot frozen in a contracted position. In addition to the discomfort of his limbs frozen in such an unnatural position, William developed muscle cramps and the stiffness that comes with being unable to move around.

What William experienced is known as “post-stroke spasticity,” a persistent and involuntary spasm of the muscles that locks limbs, hands or feet into an uncomfortable and disabling contraction. Common examples are a clenched fist or a flexed elbow, or an ankle that doesn’t bend well or a foot that turns in. In addition to loss of range of motion or ability to use the affected body part, these spasms may hurt—like a really bad Charley horse.

“Spasticity is increased muscle tension that occurs after a stroke or other injury to the brain,” explains Allison Brashear, M.D., chairman of neurology at Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina. She adds that spasticity develops as people are recovering from a stroke and can develop anywhere from three months to a year after the stroke.

Doctors estimate that the condition occurs in roughly 20 percent to 50 percent of patients, typically those who experience severe numbness or paralysis right after their stroke.

EARLY SIGNS ARE SUBTLE

Early signals may be easy to miss, Brashear warns. “It comes on gradually, and often patients and caregivers are so concerned about the other devastating effects of the stroke, such as problems with walking or talking, that the more subtle things may get overlooked. I tell my patients to look for excessive tightness, such as difficulty opening your hand or putting on your shirt.”

A stroke occurs when there is a loss of blood flow that nourishes brain tissue, due to an obstructed blood vessel (ischemic stroke), or due to a rupture of a blood vessel within the brain causing leakage from the vessel into brain tissue (hemorrhagic stroke). Either way, the resulting disability depends on the part of the brain affected. A stroke that damages the upper portion of the brain known as the motor cortex impairs the brain’s ability to properly calibrate and coordinate nerve impulses that control muscular activity, explains David Alexander, M.D., professor of neurology at the University of California, Los Angeles.

Doctors treating post-stroke spasticity focus on relieving contractions and any pain, maintaining as much range of motion as possible and relaxing the muscles in the affected areas. Treatment usually starts with physical or occupational therapy, then progresses to oral medications, and in the most stubborn cases, to injections or a pump that delivers medication directly to the spinal column.

Often several types of treatment are combined, such as physical therapy and one or more medications. There’s no one-size-fits-all therapy; a patient’s healthcare providers will consider his or her symptoms and overall health status to develop an appropriate treatment plan.

Proper management also includes treating any painful medical condition that might indirectly make the spasticity worse, for instance, urinary tract infection, gout or even ingrown toenails. The connection between pain and spasticity is not clear, but it’s thought that pain signals to the spinal cord may add to the heightened level of nerve stimulation that produces spasticity to begin with.

KEEPING THINGS MOVING

Physical therapy usually involves exercises such as stretching or walking on a treadmill, which are designed to maintain range of motion and prevent permanent muscle shortening and damage to the joints. Some people benefit from special braces or splints that hold the muscle in a normal position and keep it from contracting. Others find that hot or cold packs help their muscles relax to make moving easier. William, now 63, benefits from a water aerobics class at his local YMCA three to four days a week. Tuye, 56, usually joins him.

Of the four oral medications commonly prescribed for spasticity, three block nerve signals that tell the muscles to contract (see “How muscles relax and contract”). These are: baclofen (Lioresal, Kemstro), tizanidine (Zanaflex, Sirdalud) and diazepam (Valium). Side effects of these drugs include sleepiness, confusion and possible impairment of liver function. The fourth drug, dantrolene (Dantrium), works directly on the muscle, essentially making it unresponsive to messages coming from the nerve. Dantrolene also may cause drowsiness, as well as muscle weakness, nausea or diarrhea.

“We tend to avoid diazepam because of its sedating and addictive properties, and I avoid dantrolene because it does not work on the source of the spasticity, which is the nerve,” says Alexander, who directs UCLA’s neurological rehabilitation and research unit.

For her part, Brashear tends to avoid oral drugs because “when you swallow a pill the drug travels throughout the body, so there is a greater risk of side effects.” She adds that oral baclofen “helps people who have a more generalized spasticity, such as difficulty walking” but is not effective when the spasticity is isolated just to the fingers or the hand.

In such cases, baclofen may be administered into the spinal column through a catheter connected to a small pump implanted under the skin. While the potential for side effects is reduced and the drug is delivered directly to the neurons that are making muscles contract, the pump does have its drawbacks, Brashear says.

“[The pump] requires patients and family members [to be diligent about] refills and monitoring the dose, as well as repeated visits to the doctor.” She adds that since the pump is implanted surgically, the patient risks infection and heart or lung problems that are rare side effects of anesthesia—problems associated with any operation. And if the pump malfunctions, a repeat procedure will be needed to replace it.

 

A NEW WRINKLE FOR BOTOX

In March 2010, the Food and Drug Administration (FDA) approved the use of botulinum toxin (also known as Botox) injections to treat spasticity in the muscles of the elbow, wrist and fingers. Botox is a muscle relaxant—just as it smoothes wrinkles by relaxing the muscles of the face, it soothes spasticity by relaxing muscles in the upper extremities.

In 1996, Alexander coauthored the first study demonstrating that botulinum toxin could treat post-stroke spasticity. Six years later, Brashear and her colleagues published one of the clinical trials that persuaded the FDA to approve it for this use. “We showed that [Botox] improved patients’ ability to clean their hands, dress themselves and engage in other activities that were important to them.”

“We’ve seen significant benefits in patients who come in with, for example, a clenched fist so they can’t open their fingers to [wash] their palm, or people who can’t get their arm through a sleeve because their elbow is bent,” says Brashear.

The injections are administered every three to six months, depending on how quickly the muscle tightness returns. Side effects are related mostly to the amount of drug injected into the muscle: High doses can loosen them up too much.

LIVING WITH SPASTICITY

Left untreated, spasticity can be painful and uncomfortable. It can disrupt a patient’s sleep and make it difficult if not impossible to perform everyday tasks, such as bathing and dressing.

“One of my patients was thrilled because we helped relax her arm so she could pull her pants up by herself when she went to the bathroom,” says Brashear.

Botox injections have also helped William. Every three months, Brashear administers injections into his right arm. While the therapy “didn’t restore the full range of motion,” says Tuye, the injections coupled with physical therapy “did help him move better.”

“I could see him getting stronger,” she adds. The muscle stiffness and cramps William suffered were also significantly relieved.

Because spasticity may affect walking and balance, and even the ability to wear shoes, the condition can hamper post-stroke rehab. “Patients often are discharged from the hospital with a splint, and by the time they come back for their follow-up appointment the splint no longer fits well, due to the changes in muscle tone,” Brashear explains.

“I’ve had patients come to me who have actually had their skin break down because they can’t get their knees apart,” says Brashear.

And it’s not just patients who suffer. “I think we’ve underestimated the impact on caregivers,” adds Brashear. “Treatments benefit caregivers too, because relieving the contractions makes caring for the patients so much easier. We not only improve a patient’s ability to do things for themselves, but we also make it easier for caregivers to perform tasks such as dressing the patient.”

Still, the challenges presented by spasticity and other lingering effects of a stroke can be daunting. “I know what patients and caregivers are going through—the anger, the stress, the depression,” says Tuye. “I tell my husband every day, ‘you have to fight. You have to say, I can do it. I will do it.’ And I tell other people, ‘you can do this. Make up your mind to make a certain amount of progress every day. You can have a happy life. Don’t give up.’”

How muscles relax and contract

There is a yin and a yang to how muscles work. A neuron that originates in the brain (known as the “upper motor neuron”) and travels to the spinal cord sends a signal to a second neuron that is connected to a muscle (known as the “lower motor neuron”) to coordinate the contraction and relaxation of muscles.

When the upper motor neuron sends a signal that makes the lower motor neuron to stop contracting the muscle, it relaxes. Without that signal from the upper motor neuron, the lower motor neuron can only make the muscle contract.

When loss of blood supply caused by an ischemic stroke damages upper motor neurons in the brain, the corresponding lower motor neurons never get the signal to allow a muscle to relax. As a result, the muscle no longer has full range of motion. As the muscle remains in this contracted position, tendons and soft tissues surrounding it tighten and shorten, making stretching painful. So the patient stops trying to stretch the muscle, which causes even more tightening. Without treatment, the muscle can eventually freeze into a painful and abnormal position.

Source: American Heart Association.

 

 

 

Novartis drug Afinitor® approved by European Commission to treat patients with the most common form of advanced breast cancer

The European Commission has approved Afinitor® (everolimus) tablets* for the treatment of hormone receptor-positive (HR+), HER2/neu-negative (HER2-) advanced breast cancer (HR+ advanced breast cancer), in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor[1].
“The approval of Afinitor is an important milestone marking the first major advance for women in the European Union with hormone receptor-positive advanced breast cancer since the introduction of aromatase inhibitors more than 15 years ago,” said Hervé Hoppenot, President, Novartis Oncology. “Treatment with Afinitor gives women a new option in the battle against this advanced form of breast cancer, where there remains a significant unmet need.”

 

The approval was based on the Phase III BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) trial[1]. The randomized, double-blind, placebo-controlled, multi-center study of 724 patients found that treatment with Afinitor plus exemestane more than doubled median progression-free survival (PFS) to 7.8 months, compared to 3.2 months with exemestane alone (hazard ratio=0.45 [95% Cl: 0.38 to 0.54]; p<0.0001), by local investigator assessment[3]. An additional analysis based on an independent central radiology review showed Afinitor extended median PFS to 11.0 months compared to 4.1 months (hazard ratio=0.38 [95% CI: 0.31 to 0.48]; p<0.0001)[3]. The most common grade 3-4 adverse reactions (incidence >= 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis and diarrhea[3].

 

“By boosting the effectiveness of endocrine therapy, Afinitor significantly extends the time women with hormone receptor-positive advanced breast cancer live without tumor progression,” said Jose Baselga, MD, PhD, Chief, Hematology/Oncology, Massachusetts General Hospital and co-lead investigator of the BOLERO-2 trial. “Afinitor, the first mTOR inhibitor to be approved for this disease, has the potential to redefine the way this common form of advanced breast cancer is treated.”

 

Each year, an estimated 220,000 women globally will be diagnosed with HR+ advanced breast cancer[1],[4]. For these women, endocrine therapy remains the cornerstone of treatment, but most will eventually develop resistance to therapy[5]. This therapeutic resistance has been associated with overactivation of the PI3K/AKT/mTOR pathway[5]. Afinitor works to target the mTOR pathway in cells. mTOR is a protein that acts as an important regulator of tumor cell division, blood vessel growth and cell metabolism[5].

 

The European Commission decision follows the positive opinion adopted by the Committee for Medicinal Products for Human Use on June 21, 2012 for Afinitor for the treatment of HR+ advanced breast cancer and applies to all 27 EU member states, plus Iceland and Norway[6]. On July 20, 2012, the US Food and Drug Administration approved Afinitor in combination with exemestane in the HR+/HER2- population after failure of letrozole or anastrazole[7]. Additional regulatory submissions for Afinitor in advanced breast cancer are under way worldwide. Afinitor is also being studied in HER2-positive breast cancer in two ongoing Phase III trials.

 

About Advanced Breast Cancer

Advanced breast cancer is comprised of metastatic breast cancer (stage IV) and locally advanced breast cancer (stage III)[8]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the bones or liver[8]. Locally advanced breast cancer occurs when the cancer has spread to lymph nodes and/or other tissue in the area of the breast, but not to distant sites in the body[8].

 

It is estimated that women with metastatic breast cancer have a life expectancy of approximately 18-36 months after diagnosis and median survival for women with stage III disease is less than five years[9],[10].

 

HR+ advanced breast cancer is characterized by hormone receptor-positive tumors, a group of cancers that express receptors for certain hormones such as estrogen and progesterone. Cancer cell growth can be driven by these hormones[8]. The presence of estrogen receptor (ER) and/or progesterone receptor (PgR) is one of the most important predictive and prognostic markers in human breast cancers, and is collectively referred to as hormone receptor-positive[8].

 

About Afinitor (everolimus)

Afinitor® (everolimus) is approved in the European Union for the treatment of hormone receptor-positive (HR+), HER2/neu-negative (HER2-) advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. In the United States, Afinitor is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ breast cancer) in combination with exemestane after failure of treatment with letrozole or anastrozole.

 

Afinitor (everolimus) tablets is approved in more than 80 countries including the United States and throughout the European Union in the oncology settings of advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy, and in the United States and European Union for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin.

 

Everolimus is also available from Novartis for use in non-oncology patient populations under the brand names Afinitor® or Votubia®, Certican® and Zortress® and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

 

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

 

Afinitor® Important Safety Information

Afinitor®/Votubia® can cause serious side effects including lung or breathing problems, infections and renal failure, which can lead to death. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar and cholesterol levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed.

 

The most common adverse drug reactions (incidence >=15%) are mouth ulcers, diarrhea, feeling weak or tired, skin problems (such as rash or acne), infections, nausea, swelling of extremities or other parts of the body, loss of appetite, headache, inflammation of lung tissue, abnormal taste, nose bleeds, inflammation of the lining of the digestive system, weight decreased and vomiting. The most common grade 3-4 adverse drug reactions (incidence >=2%) are mouth ulcers, feeling tired, low white blood cells (a type of blood cell that fights infection), diarrhea, infections, inflammation of lung tissue, diabetes and amenorrhea. Cases of hepatitis B reactivation and blood clots in the lung and leg have been reported.

 

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as “potential,” “will,” “under way,” “being studied,” or similar expressions, or by express or implied discussions regarding potential new indications or labeling for everolimus or regarding potential future revenues from everolimus. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with everolimus to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that everolimus will be submitted or approved for any additional indications or labeling in any market or at any particular time. Nor can there be any guarantee that everolimus will achieve any particular levels of revenue in the future. In particular, management’s expectations regarding everolimus could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; the company’s ability to obtain or maintain patent or other proprietary intellectual property protection; government, industry and general public pricing pressures; competition in general; unexpected manufacturing issues; the impact that the foregoing factors could have on the values attributed to the Novartis Group’s assets and liabilities as recorded in the Group’s consolidated balance sheet; and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

 

About Novartis

Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, eye care, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, over-the-counter and animal health products. Novartis is the only global company with leading positions in these areas. In 2011, the Group achieved net sales of USD 58.6 billion, while approximately USD 9.6 billion (USD 9.2 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Novartis Group companies employ approximately 126,000 full-time-equivalent associates and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com.

 

References

  1. Novartis Data on File.
  2. Redmond C. Breast Cancer Hormone Therapy Options. Available at: http://christine-redmond.suite101.com/breast-cancer-hormone-therapy-options-a197304. Accessed April 27, 2012.
  3. Piccart M et al. Everolimus for Postmenopausal Women with Advanced Breast Cancer: Updated Results of the BOLERO-2 Phase III Trial. Abstract #559. American Society of Clinical Oncology 2012 Annual Meeting, Chicago, IL.
  4. Buckley N, Isherwood A, Breast Cancer. Decision Resources. 2011.
  5. Baselga J. Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer. New England Journal of Medicine. February 9, 2012.
  6. European Medicines Agency. Summary of Opinion for Afinitor. June 21, 2012.
  7. FDA Approval Announcement of Afinitor in Advanced HR+ Breast Cancer. July 20, 2012.
  8. National Cancer Institute. What You Need to Know About Advanced Breast Cancer. Available at: http://www.cancer.gov/cancertopics/wyntk/breast/WYNTK_breast.pdf. Accessed on March 8, 2012.
  9. Giordano S. Update on Locally Advanced Breast Cancer. The Oncologist, 2003.Buckley N, Isherwood A. Breast Cancer. Decision Resources, March 2011.
  10. Eniua A, Palmierib F and Perez E. Weekly Administration of Docetaxel and Paclitaxel in Metastatic or Advanced Breast Cancer. The Oncologist, 2005.

 

Source: Novartis News letter.

 

 

 

 

Loosening the Grip of Post-Stroke Spasticity.


Physical therapy and medication can help relieve this sometimes painful and disabling condition

William and Tuye Collins are coming up on an anniversary—though it’s one they’d probably rather not have. On the evening of May 10, 2000, Tuye (pronounced TOO-yee) came home from a church gathering to find her husband sprawled on the bedroom floor. He had had a major stroke that severely impaired his ability to speak and swallow.

 

As if being paralyzed on the right side weren’t hard enough, his right arm and leg were bent and his right foot frozen in a contracted position. In addition to the discomfort of his limbs frozen in such an unnatural position, William developed muscle cramps and the stiffness that comes with being unable to move around.

What William experienced is known as “post-stroke spasticity,” a persistent and involuntary spasm of the muscles that locks limbs, hands or feet into an uncomfortable and disabling contraction. Common examples are a clenched fist or a flexed elbow, or an ankle that doesn’t bend well or a foot that turns in. In addition to loss of range of motion or ability to use the affected body part, these spasms may hurt—like a really bad Charley horse.

“Spasticity is increased muscle tension that occurs after a stroke or other injury to the brain,” explains Allison Brashear, M.D., chairman of neurology at Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina. She adds that spasticity develops as people are recovering from a stroke and can develop anywhere from three months to a year after the stroke.

Doctors estimate that the condition occurs in roughly 20 percent to 50 percent of patients, typically those who experience severe numbness or paralysis right after their stroke.

EARLY SIGNS ARE SUBTLE

Early signals may be easy to miss, Brashear warns. “It comes on gradually, and often patients and caregivers are so concerned about the other devastating effects of the stroke, such as problems with walking or talking, that the more subtle things may get overlooked. I tell my patients to look for excessive tightness, such as difficulty opening your hand or putting on your shirt.”

A stroke occurs when there is a loss of blood flow that nourishes brain tissue, due to an obstructed blood vessel (ischemic stroke), or due to a rupture of a blood vessel within the brain causing leakage from the vessel into brain tissue (hemorrhagic stroke). Either way, the resulting disability depends on the part of the brain affected. A stroke that damages the upper portion of the brain known as the motor cortex impairs the brain’s ability to properly calibrate and coordinate nerve impulses that control muscular activity, explains David Alexander, M.D., professor of neurology at the University of California, Los Angeles.

Doctors treating post-stroke spasticity focus on relieving contractions and any pain, maintaining as much range of motion as possible and relaxing the muscles in the affected areas. Treatment usually starts with physical or occupational therapy, then progresses to oral medications, and in the most stubborn cases, to injections or a pump that delivers medication directly to the spinal column.

Often several types of treatment are combined, such as physical therapy and one or more medications. There’s no one-size-fits-all therapy; a patient’s healthcare providers will consider his or her symptoms and overall health status to develop an appropriate treatment plan.

Proper management also includes treating any painful medical condition that might indirectly make the spasticity worse, for instance, urinary tract infection, gout or even ingrown toenails. The connection between pain and spasticity is not clear, but it’s thought that pain signals to the spinal cord may add to the heightened level of nerve stimulation that produces spasticity to begin with.

KEEPING THINGS MOVING

Physical therapy usually involves exercises such as stretching or walking on a treadmill, which are designed to maintain range of motion and prevent permanent muscle shortening and damage to the joints. Some people benefit from special braces or splints that hold the muscle in a normal position and keep it from contracting. Others find that hot or cold packs help their muscles relax to make moving easier. William, now 63, benefits from a water aerobics class at his local YMCA three to four days a week. Tuye, 56, usually joins him.

Of the four oral medications commonly prescribed for spasticity, three block nerve signals that tell the muscles to contract (see “How muscles relax and contract”). These are: baclofen (Lioresal, Kemstro), tizanidine (Zanaflex, Sirdalud) and diazepam (Valium). Side effects of these drugs include sleepiness, confusion and possible impairment of liver function. The fourth drug, dantrolene (Dantrium), works directly on the muscle, essentially making it unresponsive to messages coming from the nerve. Dantrolene also may cause drowsiness, as well as muscle weakness, nausea or diarrhea.

“We tend to avoid diazepam because of its sedating and addictive properties, and I avoid dantrolene because it does not work on the source of the spasticity, which is the nerve,” says Alexander, who directs UCLA’s neurological rehabilitation and research unit.

For her part, Brashear tends to avoid oral drugs because “when you swallow a pill the drug travels throughout the body, so there is a greater risk of side effects.” She adds that oral baclofen “helps people who have a more generalized spasticity, such as difficulty walking” but is not effective when the spasticity is isolated just to the fingers or the hand.

In such cases, baclofen may be administered into the spinal column through a catheter connected to a small pump implanted under the skin. While the potential for side effects is reduced and the drug is delivered directly to the neurons that are making muscles contract, the pump does have its drawbacks, Brashear says.

“[The pump] requires patients and family members [to be diligent about] refills and monitoring the dose, as well as repeated visits to the doctor.” She adds that since the pump is implanted surgically, the patient risks infection and heart or lung problems that are rare side effects of anesthesia—problems associated with any operation. And if the pump malfunctions, a repeat procedure will be needed to replace it.

 

A NEW WRINKLE FOR BOTOX

In March 2010, the Food and Drug Administration (FDA) approved the use of botulinum toxin (also known as Botox) injections to treat spasticity in the muscles of the elbow, wrist and fingers. Botox is a muscle relaxant—just as it smoothes wrinkles by relaxing the muscles of the face, it soothes spasticity by relaxing muscles in the upper extremities.

In 1996, Alexander coauthored the first study demonstrating that botulinum toxin could treat post-stroke spasticity. Six years later, Brashear and her colleagues published one of the clinical trials that persuaded the FDA to approve it for this use. “We showed that [Botox] improved patients’ ability to clean their hands, dress themselves and engage in other activities that were important to them.”

“We’ve seen significant benefits in patients who come in with, for example, a clenched fist so they can’t open their fingers to [wash] their palm, or people who can’t get their arm through a sleeve because their elbow is bent,” says Brashear.

The injections are administered every three to six months, depending on how quickly the muscle tightness returns. Side effects are related mostly to the amount of drug injected into the muscle: High doses can loosen them up too much.

LIVING WITH SPASTICITY

Left untreated, spasticity can be painful and uncomfortable. It can disrupt a patient’s sleep and make it difficult if not impossible to perform everyday tasks, such as bathing and dressing.

“One of my patients was thrilled because we helped relax her arm so she could pull her pants up by herself when she went to the bathroom,” says Brashear.

Botox injections have also helped William. Every three months, Brashear administers injections into his right arm. While the therapy “didn’t restore the full range of motion,” says Tuye, the injections coupled with physical therapy “did help him move better.”

“I could see him getting stronger,” she adds. The muscle stiffness and cramps William suffered were also significantly relieved.

Because spasticity may affect walking and balance, and even the ability to wear shoes, the condition can hamper post-stroke rehab. “Patients often are discharged from the hospital with a splint, and by the time they come back for their follow-up appointment the splint no longer fits well, due to the changes in muscle tone,” Brashear explains.

“I’ve had patients come to me who have actually had their skin break down because they can’t get their knees apart,” says Brashear.

And it’s not just patients who suffer. “I think we’ve underestimated the impact on caregivers,” adds Brashear. “Treatments benefit caregivers too, because relieving the contractions makes caring for the patients so much easier. We not only improve a patient’s ability to do things for themselves, but we also make it easier for caregivers to perform tasks such as dressing the patient.”

Still, the challenges presented by spasticity and other lingering effects of a stroke can be daunting. “I know what patients and caregivers are going through—the anger, the stress, the depression,” says Tuye. “I tell my husband every day, ‘you have to fight. You have to say, I can do it. I will do it.’ And I tell other people, ‘you can do this. Make up your mind to make a certain amount of progress every day. You can have a happy life. Don’t give up.’”

How muscles relax and contract

There is a yin and a yang to how muscles work. A neuron that originates in the brain (known as the “upper motor neuron”) and travels to the spinal cord sends a signal to a second neuron that is connected to a muscle (known as the “lower motor neuron”) to coordinate the contraction and relaxation of muscles.

When the upper motor neuron sends a signal that makes the lower motor neuron to stop contracting the muscle, it relaxes. Without that signal from the upper motor neuron, the lower motor neuron can only make the muscle contract.

When loss of blood supply caused by an ischemic stroke damages upper motor neurons in the brain, the corresponding lower motor neurons never get the signal to allow a muscle to relax. As a result, the muscle no longer has full range of motion. As the muscle remains in this contracted position, tendons and soft tissues surrounding it tighten and shorten, making stretching painful. So the patient stops trying to stretch the muscle, which causes even more tightening. Without treatment, the muscle can eventually freeze into a painful and abnormal position.

Source: American Heart Association.