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P T. 2011;36(7): 396-400, 409

New Drugs/Drug News/New Medical Devices July 2011

NEW DRUGS

Dificid for C. difficile infection

Fidaxomicin tablets (Dificid, Optimer) have been approved for patients with Clostridium difficile-associated diarrhea (CDAD). C. difficile is a bacterium that can cause diarrhea and may lead to colitis, serious intestinal conditions, and death in severe cases.

A macrolide antibacterial agent, fidaxomicin is taken two times per day for 10 days with or without food. It should be used only to treat infections thought to be caused by C. difficile. People at risk for CDAD include the elderly, patients in hospitals or nursing homes, and people taking other antibiotics.

Fidaxomicin is discussed in the Pharmaceutical Approval Update column on page 410.

Source: FDA, May 27, 2011

Potiga for Seizures in Adults

Ezogabine (Potiga, Valeant/Glaxo-SmithKline) tablets are now approved for use as an adjunctive medication to treat partial seizures associated with epilepsy in adults. This is the first neuronal potassium channel “opener” indicated for patients with epilepsy. It is thought that ezogabine acts as an anticonvulsant by reducing excitability by stabilizing neuronal potassium channels in an open position.

As with other antiepileptic drugs, ezogabine may cause suicidal thoughts or actions in a small number of people. Ezogabine was approved with a patient medication guide.

Source: FDA, June 13, 2011

Nulojix After Kidney Transplantation

Belatacept (Nulojix, Bristol-Myers Squibb) has been approved to prevent acute organ rejection in adults who have received a kidney transplant. The drug is used with other immunosuppressants, including basiliximab (Simulect, Novartis), mycophenolate mofetil (CellCept, Roche), and corticosteroids. Given as 30-minute intravenous (IV) infusions, this selective T-cell costimulation blocker works with other immunosuppressants to maintain functioning of the new kidney.

A boxed warning mentions an increased risk of post-transplant lymphoproliferative disorder, a type of cancer affecting the white blood cells.

All transplant patients should limit the amount of time spent in sunlight because of the risk of skin cancer. Kidney recipients should not receive live vaccines because of the risk of infection.

Source: FDA, June 15, 2011

Generic Products

Generic Lybrel for Contraception

The FDA has approved Watson Laboratories’ levonorgestrel and ethinyl estradiol tablets, USP, 0.09 mg/0.02 mg, the generic version of Pfizer’s Lybrel tablets. The progesterone/estrogen combination oral contraceptive prevents ovulation.

Sources: PharmaLive, Pharmaceutical Business Review, June 7, 2011

Generic Levaquin for Infections

The first generic versions of Levaquin (levofloxacin, PriCara/Ortho-McNeil) have been approved to treat various infections in patients 18 years of age and older. Levofloxacin is used to treat bacterial infections of the skin, sinuses, kidneys, bladder, and prostate gland; bacterial infections that cause bronchitis or pneumonia; and inhalational anthrax.

Applications for generic levofloxacin have been approved as tablets, oral solutions, and injectable solutions for Akorn, Aurobindo Pharma, Dr. Reddy’s, Glenmark Generics, Hi-Tech Pharmacal, Lupin, Mylan, Sagent Strides, Sandoz, Teva, Torrent, and Wockhardt.

Source: FDA, June 20, 2011

DRUG NEWS

Keep Simvastatin Doses Low

Safety label changes have been announced for simvastatin because the highest approved dose (80 mg) has been linked to an elevated risk of muscle injury, particularly during the first year of use.

Simvastatin is used to reduce low-density-lipoprotein-cholesterol (LDL-C) levels. The agency is recommending that the 80-mg dose be used only in patients who have been taking this dose for 12 months or more and who have not experienced any muscle toxicity. Patients taking 80 mg of simvastatin daily had a higher risk of muscle injury compared with those who took lower doses or other statins. All statins, despite their benefits in lowering heart attack and stroke risk, carry some risk of myopathy; however, the risk is greater with the 80-mg dose. Labels are being revised for Zocor (Merck), single-ingredient generic products, Vytorin (ezetimibe/simvastatin, Merck/Schering), and Simcor (niacin/simvastatin, Abbott). If LDL-C levels are not lowered with simvastatin 40 mg, another treatment, not the 80-mg dose, should be prescribed.

Source: FDA, June 8, 2011

Actos and Bladder Cancer Risk

The FDA is requiring a label change for the diabetes medication pioglitazone (Actos, Takeda) because of a possible increased risk of bladder cancer. France and Germany are suspending sales of the drug as a result of similar concerns.

Patients who had taken the highest cumulative dose for more than one year experienced an increased risk of bladder cancer, although the risk was not elevated among pioglitazone patients overall. Information about this risk is being added to the drug’s label and to the patient medication guide.

In light of these new findings, the FDA advises that doctors not prescribe pioglitazone to patients with bladder cancer. The benefits of blood glucose control should be weighed against the drug’s unknown risks for cancer recurrence.

Sources: WebMD, June 16, 2011; Reuters, June 15, 2011

Cancer Drug Shortages Persist

Severe shortages of oncology drugs have persisted for about nine months with no sign of abating. As shortages become more prevalent, regulatory changes may be necessary to provide a long-term solution. Doctors must sometimes ration or delay treatment. Although most clinicians met patient needs despite the shortages, the supply of cancer drugs is still shrinking; 2010 was the worst year on record. Bleomycin, carmustine, cisplatin, cytarabine, doxorubicin, etoposide, leucovorin/levoleucovorin, and mechlorethamine were especially affected. Causes include increased demand and problems with raw materials.

Clinicians should be prepared to use alternatives; however, these therapies are not always available. Stockpiling drugs can worsen a shortage by depleting existing inventory. The practice is also expensive; an institution could be left with an excess of inventory if the shortage is not severe.

The FDA might have too few resources to inspect plants to allow drug production to resume after a shutdown. Companies have even produced drugs at a loss because they recognized a critical need for them. Although Teva’s California plant closed last year and is operating again, production will not reach full capacity until the end of this year.

Sources: Reuters June 8, 2011; www.nccn.org; www.ashp.org.

Vaccines for Adults Overlooked

Vaccines can be a cost-effective benefit for adults; however, unlike vaccines for infants and children, most vaccines for older patients aren’t usually stocked in the doctor’s office. Physicians may forget to check their adult patients’ vaccination histories, except perhaps for influenza and pneumonia immunizations.

Besides an annual flu vaccine and a tetanus–diphtheria booster shot every 10 years, eight vaccines are recommended for adults: influenza; tetanus-diphtheria-whooping cough (pertussis); chicken-pox (varicella); hepatitis A, B, and A/B; human papillomavirus; measles-mumpsrubella (German measles); meningococcal disease; pneumococcal disease; and shingles (herpes zoster).

Source: Associated Press, June 7, 2011

ARBs: No Sign of Cancer Risk

The FDA has announced that angiotensin receptor blockers (ARBs), which are used to control high blood pressure, do not increase the risk of cancer. In July 2010, the agency said that it would perform a safety review of these drugs after a study found a small elevated risk of cancer in patients taking an ARB compared with patients not taking an ARB. In its evaluation of more than 155,000 patients, the FDA found no evidence of a higher risk of cancer in ARB patients.

ARBs include azilsartan (Edarbi, Takeda), candesartan (Atacand, Astra-Zeneca), irbesartan (Avapro, Bristol-Myers Squibb/Sanofi-aventis), olmesartan (Benicar, Daiichi Sankyo) losartan (Cozaar, Merck), valsartan (Diovan, Novartis) telmisartan (Micardis, Boehringer Ingelheim/Abbott), and eprosartan (Teveten, Solvay).

Source: FDA, June 2, 2011

Amphetamines and Parkinson’s Disease

People who have used amphetamines such as benzedrine and dextroamphetamine (Dexedrine, GlaxoSmithKline) appear to be at an increased risk for Parkinson’s disease (PD), according to a study presented at the American Academy of Neurology meeting in April. These drugs are often prescribed for attention-deficit hyperactivity disorder, narcolepsy, and brain injuries, but they are also medications with the potential for abuse.

The study involved 66,348 people between 1964 and 1973. The participants were evaluated again in 1995. Of the participants, 1,154 had PD by the end of the study. Those who reported using either amphetamine were nearly 60% more likely to develop PD than those not taking these drugs. No increased risk was noted when the drugs were used for weight loss. Amphetamines affect the release and uptake of dopamine, the key neurotransmitter involved in PD. More research is needed to confirm the link.

Sources: Neurology Now, April/May 2011; Disabled World, February 20, 2011

Aromatase Inhibitors and Breast Cancer Prevention

In a major study, Pfizer’s exemestane (Aromasin) reduced the risk of breast cancer by more than half without the side effects that have curtailed enthusiasm for other prevention drugs.

Aromatase inhibitors have traditionally been used to prevent breast cancer recurrence in postmenopausal patients, although they are not recommended for women at average risk. Women at higher risk because of gene mutations or other reasons already have two choices for prevention, tamoxifen (Nolvadex, Astra-Zeneca) and raloxifene (Evista, Eli Lilly), but these hormone blockers carry a risk of uterine cancer and blood clots.

The study involved 4,560 women who had at least one risk factor (age 60 or older, a previous breast abnormality, preinvasive cancer, or a high score on a risk scale). They were given daily doses of exemestane or placebo. After about three years, there were 11 cases of invasive breast cancer among the treated women and 32 cases among the others, for a 65% reduction in cancer risk with the drug. The benefit was high enough that it was decided that all participants should be offered exemestane. Adverse effects were similar in both groups.

Sources: N Engl J Med, June 4, 2011; Associated Press, June 4, 2011

Levothyroxine and Fractures

What’s the best dose of levothyroxine (e.g., Synthroid, Abbott) for elderly patients with hypothyroidism? Doses commonly used in clinical practice, especially those exceeding 0.093 mg/day, may be too high for this age group.

University of Toronto researchers evaluated 213,511 adults between 70 and 105 years of age in a nested case-cohort study. The patients were either currently taking or had taken levothyroxine. Those taking high doses (more than 93 mcg/day) and medium doses (between 44 and 93 mcg/day) had more than two to three times the risk of osteoporotic fractures compared with those taking low doses (less than 44 mcg/day). The increased risk remained even after patients had stopped taking the drug for six months.

Patients with fractures were more likely than controls to have osteoporosis and to be using bisphosphonates. Both current and recent use (within the past three months) was associated with an increased risk of any fracture, particularly hip fractures.

Although the optimal dose for adults is 1.6 to 1.8 mcg/kg per day, older people often need a much lower dose to achieve euthyroidism; most guidelines recommend 0.5 mcg/kg per day. Despite this standard, levothyroxine dosages are often not adjusted as the patient ages.

Levothyroxine may also harm bone even when patients are euthyroid; the risk of vertebral fractures in older adults rises with serum thyroid-stimulating hormone (TSH) use even when TSH levels are in the lower range of normal.

Sources: BMJ, April 28, 2011; www.healthnewstrack.com

Caffeine and Coronary Artery Disease

A 200-mg capsule of caffeine can improve brachial endothelial function in patients with coronary artery disease (CAD), say researchers from Israel. In a double-blind, placebo-controlled study of 40 CAD patients and 40 healthy volunteers, caffeine also lowered markers of inflammation. Increasing serum caffeine levels by almost 4 mcg/mL reduced high-sensitivity C-reactive protein (hs-CRP) levels and increased serum adiponectin, a protein with antidiabetic and antiatherogenic properties.

Participants fasted overnight and stopped all medications for at least 12 hours and all caffeine for at least 48 hours. They were given 200-mg caffeine capsules (one cup of coffee equals 80 mg of caffeine) or placebo at 7:00 a.m. One hour after taking caffeine, they underwent brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NTG) using high-resolution ultrasound.

Although acute caffeine ingestion improved FMD in CAD patients from 5.6% to 14.6%, improvement was more marked in those without CAD (from 8.4% to 18.6%). For the two groups, acute caffeine ingestion did not significantly change NTG results. Heart rate at rest did not change in either group. Systolic and diastolic blood pressure (BP) did not change in non-CAD participants, but it did increase in CAD patients.

In another study, a cup of coffee actually decreased brachial FMD for as long as an hour or more after intake. A possible explanation is that coffee also contains polyphenols and antioxidants, which can have different effects on peripheral vasculature.

The researchers also noted some weaknesses in their own study: FMD was measured only before and one hour after caffeine ingestion. Four measurements (at baseline, and 30 minutes, one hour, and two hours afterward) might have been more ideal to describe the FMD changes. Further, few women were enrolled. Finally, the relatively large dose of caffeine (equal to 2.5 cups of coffee) used might not be generally accepted as typical consumption. Further studies are needed to investigate the effect of chronic caffeine intake on the heart.

This month’s Meeting Highlights feature also describes the effects of caffeine and coffee on BP (see page 448).

Source: Am J Cardiol 2011;107:1255–1261

Aspirin and Simvastatin Do Not Help Pulmonary Arterial Hypertension

Despite their effectiveness in treating heart disease, neither aspirin nor simvastatin (Zocor, Merck) appeared to benefit patients with pulmonary arterial hypertension (PAH), according to an NIH-funded study.

Researchers at the University of Pennsylvania expected to enroll 92 patients with PAH. Patients were to be randomly assigned to receive aspirin 81 mg or matching placebo and simvastatin 40 mg or matching placebo.

At six months, patients receiving simvastatin tended to have poorer scores in six-minute walking distance. There was no significant difference between aspirin and placebo effects. Sixty-five subjects had been randomized when the trial was terminated early after an interim analysis showed futility in reaching the primary endpoint for simvastatin.

Aspirin and simvastatin may be prescribed for the usual clinical indications in patients with PAH, but they should not be taken solely to treat PAH, according to the study authors.

Sources: Circulation, May 19 (online); Drug Discov Dev, May 18, 2011

Xeloda/Eloxatin Supports Older People With Colorectal Cancer

Elderly patients with advanced cancer have been absent from clinical trials of chemotherapy and are thus often less likely to receive life-extending treatment. Researchers from France acknowledge that choosing an effective regimen for older patients is less straightforward than for younger patients. Although 5-fluorouracil has been a mainstay of chemotherapy for patients with metastatic colorectal cancer, its usefulness for older people might be limited by the need for equipment such as an ambulatory infusion pump.

In their study, 60 subjects who were 70 years of age and older responded well to a combination of capecitabine (Xeloda, Roche) and oxaliplatin (Eloxatin, Sanofi-Synthelabo) without experiencing impaired functional ability or independence.

Treatment lasted for a maximum of six cycles. During the first three treatment cycles, capecitabine plus oxaliplatin was cautiously given at 75% of the normal dose for young adults. Capecitabine was given orally in two divided doses of 750 mg/m2 on days 1 to 14, followed by a seven-day rest. Oxaliplatin 90 mg/m2 was given intravenously over a period of two hours on day 1. Doses of both drugs could be increased by 33% (to 1,000 mg/m2 twice daily for capecitabine and 120 mg/m2 for oxaliplatin) at the start of the fourth cycle in patients with no significant toxicity.

Therapy was well tolerated, although some patients had diarrhea, constipation, and nausea. The fact that one-third of the patients were able to tolerate a higher dose supports the value of this approach.

The authors concluded that a stepwise dosing regimen was well adapted to elderly cancer patients. That, along with their ability to continue daily activities, a good safety profile, a 37% response rate, and the need for fewer hospital visits, makes this therapy an attractive option for older patients.

Source: J Geriatr Oncol 2011;2:105–111 (April)

Cyclosporine Delays Surgery For Ulcerative Colitis

Cyclosporine (e.g., Sandimmune, Novartis) not only delays the inevitable colectomy for patients with severe ulcerative colitis; it is also underused and deserves a new look—it might actually prevent the need for surgery.

At some point, approximately 15% of patients with severe ulcerative colitis are admitted to the hospital with a severe flare, for which they often receive intravenous (IV) steroids or cyclosporine. From 74% to 91% of patients avoid colectomy in the short term, and 42% to 70% avoid colectomy in the long term (1.5 to 13 years). The wide range reflects the small size of the studies and the variability in dosing and administration.

Researchers from the United Kingdom analyzed data for 38 patients who received cyclosporine for an acute, steroid-refractory flare of colitis over a period of nine years. Upon admission, 20 patients were taking oral steroids, eight were taking a thiopurine, and seven received no treatment. Oral cyclosporine was started at a median of eight days after admission (range, 1–28 days). Most patients received 4.5 to 8.3 mg/kg.

Of the 36 patients who received cyclosporine, 15 had a colectomy during the follow-up period of 11 to 118 months. Eleven surgeries were performed because of a lack of response in the acute phase. However, of the 25 patients who were discharged without surgery who were still receiving cyclosporine, 21 (84%) did not yet need a colectomy after a median follow-up of 3.8 years.

The four patients who did have surgery did so three to eight months after discharge. One patient had stopped all medications to seek alternative therapies, one did not respond to immunomodulators, and one experienced drug-related adverse effects, including retinopathy. Cyclosporine was used as a bridging therapy to azathioprine (Azasan, Salix; Imuran, GlaxoSmithKline). Azathioprine was started at a median of five weeks after hospital discharge.

Cyclosporine was tolerable and safe, which the researchers attribute to careful management of the transition from cyclosporine to azathioprine, monitoring by nurses trained in irritable bowel disease, and careful adjustment of drug doses according to the patient’s colitis symptoms and signs of toxicity.

Source: J Crohns Colitis 2011;5:91–94 (April)

RESEARCH NEWS

Temodar Plus a PARP Inhibitor in Colon Cancer

A new regimen for metastatic colon cancer appears to benefit patients even after other therapies have failed, say research physicians at Georgetown University. However, their study was small and did not include a comparison arm, thus warranting further investigation.

The team combined a poly (ADP ribose) polymerase (PARP) inhibitor with a chemotherapy agent, temozolomide (Temodar, Merck). The PARP is a key part of a cell’s DNA repair apparatus and protects normal cells against DNA damage. Cancer cells become resistant to chemotherapy partly by increasing PARP expression and rapidly repairing DNA damage intentionally caused by chemotherapy. PARP inhibitors are designed to overcome a cancer cell’s ability to repair the damaged DNA.

The phase 2 study enrolled 49 patients with inoperable meta static disease. Doctors gave patients temozolomide, a potent DNA-damaging chemotherapy, along with a PARP inhibitor, ABT-888 (veliparib, Abbott) to try to diminish the ability of these cancer cells to fix the damage inflicted by the temozolomide, thus destroying the cancer cells. The drug combination controlled cancer growth for nearly six months in 23% of the patients. Two patients had a partial response.

The researchers were able to collect samples of the patients’ tumors for further molecular analysis. By testing tissue samples and identifying their molecular fingerprints, they hope to identify which patient groups would be likely to respond to the combination.

Sources: J Clin Oncol 29:2011 (Suppl; Abstract 3502); Drug Discov Dev, May 19, 2011

DEVICE NEWS

Silicone Implants: Update

When the FDA allowed silicone gel-filled breast implants to return to the market in November 2006, it required manufacturers to conduct studies to learn more about the long-term safety of the devices. A new FDA report still suggests that the implants are safe, when used as intended, but states that risks are involved. The implants may need to be removed within 10 years in as many as 20% of augmentation patients and in as many as 50% of reconstruction cases. The devices have not been found to cause breast cancer, reproductive problems, or connective tissue disease, but longer studies are needed to completely rule out these complications. Patients should continue to undergo routine imaging to detect silent ruptures three years after receiving the implants and every two years after that.

A redesigned Web site is available at www.fda.gov/breastimplants.

Source: FDA, June 22, 2011

NEW MEDICAL DEVICES

Marvin M. Goldenberg, PhD, RPh, MS

Name: Solesta Gel

Manufacturer: Oceana Therapeutics, Edison, N.J.

Approval Date: May 27, 2011

Purpose: Solesta is a sterile, injectable gel that is used as a bulking agent to treat patients 18 years of age with fecal incontinence when dietary modifications, fiber therapy, or antimotility drugs have been unsuccessful.

Description: The gel is injected just beneath the anal lining with the aim of expanding area tissue. This treatment may facilitate better control of bowel movements.

Benefit: Approximately 2% of people, or more than 5.5 million Americans, have fecal incontinence. Women may be affected if they experience an injury during childbirth. The gel provides a minimally invasive therapy for this difficult-to-treat condition.

Precautions: Solesta should not be used in patients who have inflammatory bowel disease, immunodeficiency disorders, a history of pelvic radiation, significant rectal prolapse, an active infection, bleeding, anorectal tumors or malformations, rectal distended veins, an anorectal implant, or an allergy to hyaluronic acid. Adverse effects have included injection-site pain and bleeding.

Sources: FDA; www.medscape.com/viewarticle/743588?sssdmh=dm1.691110&src=nl_newsalert

Name: Xience Nano Everolimus Eluting Coronary Stent System

Manufacturer: Abbott, Abbott Park, Ill.

Approval Date: June 1, 2011

Purpose: The Xience Nano stent system is used to treat coronary artery disease (CAD) in blood vessels as small as 2.25 mm in diameter. Placement of the stent within the narrowed coronary artery improves blood flow. The device is based on the same platform as the Xience V system.

Description: A thin coating of everolimus is included on the stent’s surface. The stent is mounted on a folded balloon attached to a catheter delivery system to be placed into a coronary artery. A catheter with a small balloon mounted on the end is inserted into a blood vessel in the groin or arm and advanced into a coronary artery.

The catheter is positioned at the narrowed portion of the artery and the balloon is inflated. As the balloon inflates, it stretches the coronary artery wall and compresses the plaque. The balloon is deflated, and the catheter is removed from the artery. The stent remains implanted within the coronary artery to keep it open. Everolimus is gradually released into the artery wall around the stent to prevent vessel re-narrowing.

Benefit: Small blood vessels often are associated with restenosis after stent insertion. With its cobalt chromium stent design and everolimus coating, this Xience Nano stent system prevents abnormal tissue growth and allows for the optimized treatment of CAD in patients with small blood vessels. The FDA’s approval of the device was supported by results from the SPIRIT small-vessel trial.

Sources: www.fda.gov; www.pmp-news.com

Name: High Flo RMS Subcutaneous Needle Sets

Manufacturer: Repro-Med Systems, Inc., Chester, N.Y.

Approval Date: June 1, 2011

Purpose: The needle sets are used to deliver medications to subcutaneous tissue.

Description: The custom-designed needles are approximately 26-gauge with a smaller outside diameter than the typical 24-gauge needles. The sets are available in single, double, triple, and quadruple configurations. As many as eight needles can be used for a single infusion. Needle lengths are 6 mm, 9 mm, and 12 mm. The sets are also sold in Canada and Europe.

Benefit: Patients report less pain during needle insertion and during lengthy infusions. Flow rates are also faster. When used in multi-needle sets, the drug is distributed equally to all needles.

Sources: http://drugstoday.info; www.qmed.com

Device Recall

Boston Scientific Corp. has recalled 110,000 of its iCross Coronary Imaging Catheters used in ultrasound evaluation of the blood vessels. The Class I recall was initiated because of the occurrence of catheter tip detachments resulting from embrittlement of the catheter material. The recall does not affect patients who have already been treated with the devices; the potential problem occurs during the procedure.

Health risks associated with this type of device failure may include vessel-wall injury, thrombosis, a retained foreign body, myocardial infarction, and death. Almost 29,700 units have been distributed in the U.S., Puerto Rico, Trinidad, Tobago, and the American Virgin Islands.

In May, the company had indicated that the Atlantis SR Pro Imaging Catheter could be used as a replacement. In June, however, it was found that the catheter tip could break inside the patient, causing blood vessel injury, a heart attack, or other serious events. The recall has been extended to include this catheter.

Sources: Reuters, June 14, 2011; www.ptca.org/news/2011/0528_BSCI_ICROSS.html; HeartWire, www.theheart.org, May 30, 2011; Massachusetts Medical Devices, May 31, 2011, www.massdevice.com