Medicolegal Issues

Busy Season in Pharma


It’s been an active summer for pharmaceutical firms, who’ve been particularly busy adding and removing products from the marketplace and providing fresh information to professional users. Here’s a roundup of vital information that has emerged.

Market Withdrawals

Because of an increased risk of death associated with aprotinin injection (Trasylol) compared with either aminocaproic acid or tranexamic acid, Bayer Pharmaceuticals has removed all remaining stocks of the agent from the U.S. market. Subsequent access to aprotinin injection will be limited to investigational use based on a special treatment protocol. For more information on this, call (888) 842-2937.

Meanwhile, nedocromil sodium inhalation aerosol (Tilade) has been discontinued. Once current supplies are depleted from pharmacies, it no longer will be available. A number of factors led to the decision, including the inability to find a qualified manufacturer of the chlorofluorocarbon propellant.


  • Calcipotriene 0.005%/betamethasone dipropionate 0.064% Topical suspension (generic Taclonex) for scalp psoriasis;
  • Drospirenone/ethinyl estradiol tablets (generic Yasmin) oral contraceptive;
  • Paroxetine CR 12.5 and 25 mg tablets (generic Paxil CR). Mylan has 180 days of marketing exclusivity;
  • Ropinirole tablets (generic Requip);
  • Zaleplon capsules (generic Sonata).

New Approvals

Certolizumab pegol (Cimzia) injection has been approved by the Food and Drug Administration (FDA) to treat adults with moderate to severe Crohn’s disease who have not responded to conventional therapies. It is a pegylated tumor necrosis factor antagonist. The most common side effects are headache, upper respiratory infections, abdominal pain, injection site reactions, and nausea. It is dosed as an initial 400 mg SC injection followed by 400 mg SC injections at weeks two and our.

A maintenance regimen of 400 mg subcutaneous every four weeks is recommended for patients who obtain a clinical response after the initial three injections. The drug is available as a package that includes everything required to reconstitute and inject the drug (also two vials of drug, each with 200 mg Cimzia). Patients need to be evaluated for increased infection risk and opportunistic infections. Patients should be screened for tuberculosis prior to commencing therapy.

Desvenlafaxine 50 mg tablets (Pristiq), a serotonin-norepinephrine reuptake inhibitor (SNRI), have been FDA approved for the treatment of adults with major depressive disorder. It is dosed once daily. To reach the therapeutic dose, titration is unnecessary. Dose adjustments are necessary for severe renal impairment or end-stage renal disease patients, where the dose should be adjusted to 50 mg every other day. Nausea, dizziness, hyperhidrosis, constipation, and decreased appetite are the most common side effects.

Lubiprostone capsules (Amitiza) have been FDA approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in women 18 or older. Common side effects are nausea, diarrhea, and abdominal pain. It is dosed as 8 mcg twice a day with food and water. Patients should be periodically assessed for therapy continuation need.

Methylnaltrexone bromide (Relistor) has been FDA approved to assist in restoring bowel function in patients who are continuously receiving opioids for pain management and have late-stage, advanced illness. It works by blocking opioid entrance into smooth muscle. It is administered by injection as often as needed, but not to exceed more than one dose in a 24-hour period.

New Indications

Aripiprazole (Abilify) has received a number of new indications from the FDA, mostly in adolescents and children. In adults, it has received approval as an adjunctive treatment to either lithium or valproate for patients age 10 or older with manic and mixed episodes associated with bipolar I disorder with or without psychotic features. When used as monotherapy for bipolar I disorder in adults, the recommended starting dose for these indications in adults is 15 mg/day with a target dose of 30 mg/day.

Other new indications include:

  • Lisdexamfetamine dimesylate (Vyvanse) once-daily prodrug of dexamphetamine has been FDA approved for the treatment of attention deficit/hyperactivity disorder (ADHD) in adults;
  • Olopatadine hydrochloride (available as the ocular product Patanol) is now available as a nasal spray (Patanase). It was FDA approved for treatment of the symptoms of seasonal allergic rhinitis in patients age 12 or older;
  • Quetiapine (Seroquel) has been FDA approved for maintenance treatment in patients with bipolar I disorder. Quetiapine was already approved for the treatment of schizophrenia and depressive or manic episodes; and
  • Risedronate sodium 150 mg tablets (Actonel) have been FDA approved as a once-monthly dose to treat postmenopausal osteoporosis.

New Information

Varicella zoster vaccine, live, attenuated (Zostavax): The Centers for Disease Control and Prevention recommends that all adults age 60 or older be vaccinated against herpes zoster with this new vaccine. The recommendation includes patients with a prior shingles episode and those with chronic medical conditions.

Zoster vaccination is not indicated to treat acute zoster, to prevent people with acute zoster from developing post-herpetic neuralgia (PHN), or to treat ongoing PHN. Before administering zoster vaccine, patients do not need to be asked about their history of varicella (chickenpox) or to have varicella immunity testing. It is administered as a single subcutaneous 0.65 mL dose in the deltoid region of the arm. A booster dose is not licensed for the vaccine.

Medication Error Warning

The Institute for Safe Medication Practices (ISMP) has described increased reports of mixups between U-100 and U-500 insulin. These errors can result in dangerous hyperglycemia or hypoglycemia. Mistakes have occurred when prescribers accidentally selected U-500 regular insulin (R) from computer order entry screens instead of U-100.

Potential reasons for this error:

  • The two dosage forms appear one line apart on the screen, making it easy to select the wrong one;
  • Depending on the screen size, you may only see the first few words of the product listing, so the drug concentration may not be visible;
  • Since use of U-500 insulin is uncommon, you may assume the only listed R insulin is U-100 and not look for the drug’s concentration.

ISMP suggests that use of U-500 insulin has increased due to the obesity epidemic, use in insulin pumps, and tight glucose control protocols in the hospital. ISMP says the major suppliers of these computer systems have agreed to add the word “concentrated” on their selection screens, after “insulin” and before U-500, which should help solve the problem.

New Warnings

The acquired immunodeficiency syndrome (AIDS) drugs abacavir (Ziagen) and didanosine (Videx) are being evaluated by the FDA for a possible link to increased risk of myocardial infarction (MI). This is related to the analyses of data collected from “The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study,” which is a large, international observational study of 33,347 HIV-1 infected patients evaluating short- and long-term adverse effects of anti-HIV treatments. The excess risk of MI in patients taking these agents appeared to be greater in patients with other heart disease risk factors. This is an ongoing review.

Meanwhile, the anemia drugs darbepoetin alfa (Aranesp) and epoetin alfa (Epogen/Procrit) have received a boxed warning regarding increased mortality and/or more rapid tumor progression in patients with cancer that are receiving these agents. The warnings section of the package labeling also was updated with additional study information.

Becaplermin gel (Regranex) is a recombinant form of human platelet-derived growth factor FDA approved for treating lower-extremity diabetic neuropathic ulcers. The FDA is evaluating the possibility of an increased cancer risk in diabetic patients who apply becaplermin gel directly to foot/leg ulcers. A recent study involving patients with no previous history of cancer had a greater risk of dying from cancer if they were prescribed becaplermin three or more times. The FDA believes there may be evidence of an increased cancer death risk in patients who had repeated becaplermin treatments.

Montelukast (Singulair) is undergoing a safety review regarding a possible association between it and behavior/mood changes, suicidality, and suicide. However, it may take up to nine months to complete the review. Other leukotriene receptor antagonists also are being evaluated (e.g., zafirlukast, zileuton).

Mycophenolate mofetil (MMF) and the ester of the active metabolite mycophenolic acid (MPA), known as Cellcept and Myfortic, have received an FDA alert regarding reports of infants born with serious congenital anomalies. These anomalies have included microtia, and cleft lip and palate. These women were taking these drugs to prevent organ rejection following transplant, however, some women were receiving the drugs to manage systemic lupus erythematosus (SLE), and erythema multiforme. These women were receiving the agents before their pregnancies and continued into the first trimester or until the pregnancy was detected. Both MMF and MPA increase the risk of spontaneous abortion in the first trimester and can cause congenital malformations in the children that received the drugs in utero.

The FDA and the manufacturer of natalizumab injection (Tysabri) have informed healthcare professionals of reports of clinically significant liver injury (e.g., markedly elevated serum hepatic enzymes, elevated total bilirubin) within six days of starting natalizumab. The agent is FDA approved to treat multiple sclerosis and Crohn’s Disease. Natalizumab should be discontinued in patients with jaundice or other evidence of significant liver injury. Physicians need to inform patients that natalizumab may cause liver injury. TH

Michele B. Kaufman, PharmD, BSc, RPh, is a registered pharmacist based in New York City.

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