N.C. Firm Recalls Heparin Flush Syringes

BETHESDA, MD, 21 December 2007 — AM2PAT Inc. in North Carolina is recalling lot 070926H of the firm's heparin-containing flush-solution product because of contamination with Serratia marcescens, according to a press release dated December 20 and circulated today by FDA.

The company, which does business as Sierra Pre-Filled Inc., described the product as 12-mL syringes containing 5 mL of 100-unit/mL "Heparin Lock Flush Solution USP."

An Associated Press interview earlier this week with the firm's president suggested that, by December 18, none of lot 070926H remained on the market.

According to AM2PAT's press release, the Centers for Disease Control and Prevention tested the flush solution from several unopened syringes and found evidence of Serratia marcescens.

In addition, the press release states, "It appears from an ongoing Food and Drug Administration (FDA) inspection of AM2 PAT, Inc.'s facility that the firm is not in compliance with the Quality System regulation and failed to have adequate controls to ensure necessary sterility of its pre-filled syringes."

AM2PAT brought its flush-solution product to market through FDA's 510(k) premarket notification process for medical devices. The company in July 2003 submitted paperwork claiming that the product was substantially equivalent to four heparin flush-containing syringe products already on the market. FDA agreed in December 2003.

According to the "510k Summary" of AM2PAT's paperwork, "Test data have been generated for stability and container/closure suitability." The summary does not state that the firm had test data substantiating that the product is sterile.

FDA since mid-2006 has regulated all heparin-containing flush solutions as medical devices. Until that time, some of the flush solutions entered the market through FDA's drug-approval process and others, like the flush-containing syringes produced by AM2PAT, entered through the premarket notification process.

Viagra Helps COPD Patients Control Pulmonary Blood Pressure

The drug sildenafil, popularly known as Viagra, may help people with chronic obstructive pulmonary disease control the illness-related blood pressure spikes in the heart's pulmonary artery, a new study found.

The medication, in addition to its use as a popular treatment for impotence, has already been approved by the U.S. Food and Drug Administration for the treatment of the chronic version of such blood pressure spikes, known as pulmonary arterial hypertension (PAH). The drug has been marketed specifically for this purpose under the trade name Revatio. Another drug -- bosentan -- is also approved for similar purposes.

The new research suggests that sildenafil may help all chronic obstructive pulmonary disease (COPD) patients -- even those not diagnosed with full-blown PAH -- who experience potentially dangerous pulmonary arterial blood pressure increases both at rest and following exercise.

The research was led by Dr. Sebastiaan Holverda of the department of pulmonary medicine at VU University Medical Center in Amsterdam, the Netherlands. Holverda and his VU colleagues were to present their findings Wednesday at a Salt Lake City meeting organized by the journal Chest.

According to the American Lung Association, COPD is actually a catch-all for two lung diseases that often strike in tandem -- chronic bronchitis and emphysema. In both cases, airflow is obstructed, impeding normal breathing.

Smoking is the leading cause of COPD, responsible for between 80 percent and 90 percent of all cases in the United States. More than 11 million Americans are estimated to have the illness, and more than 122,000 die from it each year. Women appear to be slightly more at risk than men.

There's no known cure for the disease, and medications primarily take aim at symptom relief and slowing the progressive disability the illness brings.

Pulmonary hypertension -- the incurable condition of continuous high blood pressure in the pulmonary artery located in the right ventricle of the heart -- is one of many serious complications that can strike COPD patients. PAH causes the artery, which is responsible for delivering blood from the heart to the lungs, to work harder than normal. A weakening of the heart muscle can ensue over time, increasing the risk of heart failure and even death.

The Dutch researchers noted that pulmonary hypertension is typically mild to moderate among COPD patients but is particularly aggravated while exercising.

Faced with the combined COPD-PAH threat, the Dutch team explored the potential benefit of treating at-risk chronic obstructive pulmonary disease patients with sildenafil both while at rest and during exercise. The drug works by shifting the activity of an enzyme called phosphodiesterase, reducing arterial blood pressure by dilating the smooth muscle of blood vessels that line the lungs. As these vessels expand, blood flow increases, the researchers explained.

The study authors focused on 12 patients who had been diagnosed with chronic obstructive pulmonary disease and were suspected of having PAH. Throughout the study, right heart blood pressure was tracked among all 12 patients by inserting a thin plastic tube into the pulmonary artery -- a procedure known as cardiac catheterization. Cardiac blood pressure was measured at rest and just after all the patients cycled for three minutes.

Then, the study participants were given 50 milligrams of oral sildenafil; 45 minutes later, resting and post-exercise blood pressure readings were taken again.

Holverda and his colleagues found that half the patients had PAH. But, both non-PAH and PAH patients experienced significant cardiac blood pressure increases when exercising.

Sildenafil appeared to control such increases after exercise, reigning in pulmonary blood pressure to markedly lower levels -- higher than at rest, but lower than non-medicated post-exercise readings. And, the non-PAH patients appeared to experience pulmonary blood pressure reductions after taking the drug, both while resting and exercising.

The authors concluded that the drug may help COPD patients -- whether they have developed PAH or not -- quickly control their pulmonary blood pressure in some situations.

Dr. Bartolome R. Celli, chief of pulmonary care at St. Elizabeth's Medical Center in Boston, applauded the Dutch study but called for more research.

"Pulmonary arterial pressure -- when it is elevated -- is a poor prognostic sign and reducing its levels should be of help," he said. "However, more testing is needed to see if those changes in pulmonary arterial pressure are translated into better clinical outcomes and not into any unwanted side effects."

Defer Hib Vaccine Booster in Most Children, CDC Says

BETHESDA, MD, 19 December 2007 — Issues related to a recall of Merck & Co.'s Haemophilus influenzae type b (Hib) conjugate vaccines will cause them to be in short supply, prompting federal officials today to recommend temporary changes to the childhood immunization schedule.

Interim recommedations (PDF) from the Centers for Disease Control and Prevention (CDC) call for deferring booster vaccination of most young children, who would ordinarily be administered a dose at 12–15 months of age.

The problem stems from a recent recall of several lots of Merck's PedvaxHIB and Comvax vaccines whose sterility cannot be guaranteed.

The recalled lots of vaccine are potent, and children who have already been vaccinated with the material do not require revaccination, CDC stated.

According to CDC, Merck has temporarily ceased production of the vaccines and does not expect new vaccines to be available until late next year.

Merck is the only U.S-licensed manufacturer of Hib capsular polysaccharide vaccines that are conjugated to a meningococcal protein. Labeling for the products states that they are for primary vaccination of infants at two and four months of age and booster vaccination at 12–15 months.

Two additional tetanus-conjugated Hib vaccines—ActHIB, a Hib-only vaccine, and TriHIBit, a combination product—are available from Sanofi Pasteur. ActHIB is suitable for the primary vaccination series, but if an infant is administered that vaccine the two- or four-month dose, a third dose is required at six months of age to complete the primary series.

CDC's childhood immunization schedule for 2007 recommends that TriHIBit be used only for booster vaccination in children 12 months or older, not as a part of the primary vaccination series.

The interim recommendations state that health care providers can use a tetanus-conjugate Hib vaccine to complete the primary series in children who are at low risk for meningococcal disease if they previously received one dose of a Merck Hib vaccine.

Children who are at increased risk for meningococcal disease, including those with asplenia, sickle-cell disease, HIV infection, cancer, or an immune deficiency, should receive the full Hib vaccine series during the vaccine shortage, including the 12–15-month booster, according to CDC. The agency stated that PedvaxHIB, ActHIB, or TriHIBit, can be used for booster vaccination of these children.

CDC stated that American Indian and Alaska Native children are at high risk for meningococcal disease, and the risk is higher in children who do not receive a meningococcal conjugate vaccine for the first dose of the Hib vaccine series. The agency recommends that health care providers who serve these communities stock and use only meningococcal conjugate vaccines and to continue vaccinating these children as recommended in the normal schedule.

Meningococcal conjugate vaccines against Hib are part of CDC's national stockpile, and the agency stated that it will make these products available for use in American Indian and Alaska Native communities.

According to CDC, Sanofi plans to increase its production of Hib vaccines, but the company will not be able to provide enough vaccine to fully vaccinate all children during the shortage.

The agency has asked health care providers not to stockpile Hib vaccines and to order only enough to meet "immediate needs."

New Beta-Blocker Gets FDA Approval

"BETHESDA, MD, 18 December 2007 — A new beta-blocker from Mylan and Forest Laboratories was approved Monday for marketing in the United States, FDA announced.

Nebivolol hydrochloride will be marketed as Bystolic tablets, according to Forest Laboratories, which will sell the product in this country. FDA-approved labeling for the product is available at www.bystolic.com.

Bystolic is expected to be available in pharmacies next month, according to Forest.

The labeling for nebivolol states that the drug is indicated for use alone or in combination with other medications for the treatment of hypertension.

The labeling states that nebivolol acts as a "preferentially" selective beta-1-adrenergic receptor blocker in patients who extensively metabolize cytochrome P-450 (CYP) isoenzyme 2D6 and at doses of 10 mg or less. At higher doses and in the small proportion of the population who are considered poor metabolizers of CYP2D6, nebivolol inhibits both beta-1 and beta-2 receptors.

The drug does not block alpha-1 adrenergic receptors at "clinically relevant" dosages, according to the labeling.

In placebo-controlled clinical trials, the most common adverse events reported by nebivolol users were headache, fatigue, and dizziness. Spontaneous postmarketing reports from countries outside the United States describe numerous adverse events, including abnormal liver function, pulmonary edema, kidney failure, atrioventricular block, and rashes, that occurred during nebivolol use.

Nebivolol is contraindicated in patients with severe bradycardia, cardiogenic shock, decompensated heart failure, or second-degree or greater atrioventricular block, and in patients with sick sinus syndrome who do not have a pacemaker.

The drug is also contraindicated in patients with severe liver impairment.

Initiation of nebivolol therapy in most patients should begin with 5 mg taken once daily with or without food, according to the labeling. The dosage may be adjusted upward every two weeks to a maximum daily dose of 40 mg to further lower blood pressure.

The labeling recommends that patients with severe kidney impairment or moderate liver impairment begin with a 2.5-mg daily dose of nebivolol, with cautious upward adjustments, if necessary.

Dosage adjustments are not needed in patients who are poor metabolizers of CYP2D6, according to the labeling.

Nebivolol is formulated as 2.5-, 5-, and 10-mg tablets for oral administration. All strengths will be packaged in bottles of 30 or 100 tablets, and the two higher doses will also be sold in unit-dose packages. The product should be stored at controlled room temperature.

FDA Approves New Antipsychotic

BETHESDA, MD, 20 December 2006 — FDA and Janssen L.P. today announced the approval of paliperidone extended-release tablets for the treatment of schizophrenia.

Paliperidone, which will be marketed as Invega, is the active metabolite of the atypical antipsychotic drug risperidone. Janssen expects to make the drug available in January.

The FDA-approved labeling (PDF) for paliperidone states that the drug's mechanism of action is unknown but may be related to dopamine- and serotonin-receptor antagonism.

According to Janssen, paliperidone proved superior to placebo for symptom improvement during clinical trials. The company stated that paliperidone bested placebo for improvement in the Personal and Social Performance Scale—a validated instrument for assessing social functioning—and is currently the only schizophrenia treatment whose labeling is allowed to make this claim.

The most common adverse events reported in clinical trials of paliperidone were movement disorders, restlessness, drowsiness, and heart palpitations, according to FDA.

The product's labeling contains a boxed warning advising against the use of paliperidone for the treatment of elderly patients with dementia-related psychosis, because this population faces an increased risk of death during treatment with atypical antipsychotic drugs. Other class-related warnings and precautions in the labeling include descriptions of patients' risk for neuroleptic malignant syndrome, hyperglycemia, adverse cerebrovascular events, seizures, and hyperprolactinemia.

The labeling also describes a "modest increase" in the corrected QT (QTc) interval among patients who received paliperidone and states that the drug should not be used in combination with other drugs associated with prolongation of the QTc interval. Patients with congenital long QT syndrome or a history of cardiac arrhythmias should likewise avoid using paliperidone.

Patients who have a history of hypotension should be monitored during paliperidone therapy because of an association between use of the drug and orthostatic hypotension and loss of consciousness, according to the labeling.

Paliperidone will be available in 3-, 6-, and 9-mg tablets packaged in bottles of 30 and 350 each and in 100-count unit dose packs.

The tablets are constructed using a complex process to create an osmotically active trilayer core. Osmotic pressure controls release of the drug from the tablets, which must be swallowed whole to achieve the intended extended-release performance. Because of their construction, the tablets do not totally disintegrate in the gastrointestinal tract, and tablet shells may appear in patients' stool.

The recommended starting dosage of paliperidone is 6 mg taken each morning. Higher dosages are associated with "a general trend for greater effects" that must be set against a dose-related increase in adverse events, according to the labeling.

Patients with mild to moderate liver impairment do not require a downward dosage adjustment when beginning treatment with paliperidone. Such adjustments are required in patients with impaired kidney function, who should receive no more than 6 mg of paliperidone per day, the labeling states.