DID - Nov. 14, 2008 Issue

Vol. 7 No. 224

FDA Is Considering REMS for Opiate Drugs

The FDA is considering implementing a risk evaluation and mitigation strategy (REMS) for opiate drugs, but the issue is still in flux, according to an FDA director.

“At this time, we’re still having a lot of extensive internal discussions about how to implement a REMS, if at all, to what degree, [and for] what opiate drug products,” Bob Rappaport, director of the Division of Anesthesia and Rheumatology Products, said Thursday.

There are risk management plans in place for most of the potent opiates, such as surveillance programs and distribution of educational materials, but implementing an overarching REMS for such products is a difficult task that would take some time to complete, Rappaport said at a joint meeting of the Anesthetic and Life Support Drugs and Drug Safety and Risk Management advisory committees.

The meeting was held to discuss Pain Therapeutics and King Pharmaceuticals’ investigational painkiller Remoxy XRT (oxycodone). The committees were not asked whether the drug should be approved but whether its novel tamper-resistant properties would deter people from abusing it as other extended-release oxycodone products have been misused.

No official vote was taken, but the committee split over whether the available data show that the product is less susceptible to abuse and misuse.

The FDA also asked the committee to weigh in on the surveillance programs available to monitor whether painkillers are being abused and how to best incorporate information on the tamper-resistant properties of the drug into physician labeling without leading physicians to believe the product is less addictive.

FDA briefing documents for the meeting show that the agency planned to ask the committee to discuss whether the proposed surveillance program would detect misuse of the product (DID, Nov. 13). But the committee was asked only to discuss the adequacy of tools meant to assess how a novel, tamper-resistant opioid would affect misuse, diversion and abuse of such products.

No Good Answers

After the committee hearing, Rappaport said he did not hear any good answers to those two questions.

Leonard Paulozzi, a committee member and medical officer at the U.S. Centers for Disease Control and Prevention, said the use of mortality data was not a good indicator of abuse, and autopsy data did not show which brand of pharmaceutical was used by people who died after a drug overdose.

Committee member Timothy Leasar, director of pharmacy at Albany Medical Center, said he wondered how the drug would act if the product were soaked in soda for six hours or if abusers would double the amount of Remoxy they take to get the euphoric effect.

He also said Remoxy XRT was probably the best extended-release oxycodone drug and that it would help prevent medical errors.

Safety Problems With Abuse

Committee members expressed concern about data from preclinical testing that showed that injecting Remoxy XRT could cause heart and lung damage. Drug addicts often inject potent opioids.

Ping Ji, a senior clinical pharmacologist with the FDA’s Office of Clinical Pharmacology, said studies show the controlled-release properties of Remoxy XRT are compromised when the drug is crushed and the active ingredient is extracted with ethanol. Controlled release also was compromised when the capsules were chewed or absorbed in the cheek.

But the FDA is basing its assessment on data that do not incorporate a time element. For example, it takes significantly less time to extract a high dose of oxycodone from an alcohol solution than it does from Remoxy XRT.

Sharon Hertz, deputy director of the Division of Anesthesia and Rheumatology Products, told the committee that the agency wanted members to understand all potential facets of the product, and that exposure to high doses of the drug is a safety concern, even if it takes hours of chewing the pill to get a dose-dumping effect.

Nadav Friedmann, chief operating officer for Pain Therapeutics, countered that the product is designed to deliver its active ingredient, and if the drug is soaked in alcohol long enough, it will extract all the active ingredient. He said the delay in how long it takes to extract the active ingredient was important. — Christopher Hollis


Gardasil Not Just for Girls Anymore, Study Shows

Merck’s cervical cancer vaccine Gardasil was effective in preventing external genital lesions caused by human papillomavirus (HPV) in boys and men age 16–26, according to a Phase III clinical trial.

The trial enrolled roughly 3,400 heterosexual and 600 homosexual males who had not been infected with at least one of the HPV types — 6, 11, 16 or 18 — that the vaccine is designed to protect against. The patients were followed until one month after receiving their third dose of the vaccine or a placebo.

Gardasil reduced external genital lesions in the active arm of the trial by 90.4 percent, a primary endpoint. The vaccine also achieved statistical significance on its secondary endpoints: reducing persistent HPV infection, for which it was 85.6 percent effective, and reducing “anytime” HPV DNA detection, at which it was 44.7 percent effective.

No vaccine-related serious adverse events were reported, but there were slightly more injection-site adverse events in the vaccine group — 60.1 percent, compared with the placebo group at 53.7 percent.

Merck plans to submit a Gardasil sBLA to the FDA by the end of the year for its tested primary indication. The vaccine currently is not approved for males in the U.S.

Gardasil is indicated for use in girls and young women age 9–26 for the prevention of cervical, vulvar and vaginal cancers caused by HPV types 16 and 18, genital warts caused by HPV types 6 and 11 and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18. — Martin Gidron


AMAG Iron-Replacement Therapy Moves Nearer Approval

The FDA has designated AMAG Pharmaceuticals’ resubmission for its iron-deficiency anemia treatment ferumoxytol as a complete Class 1 response and plans to make a marketing approval decision by Dec. 30.

Ferumoxytol has the potential to replace IV iron infusion treatments, AMAG spokeswoman Kristen Galfetti told DID Thursday. “What we know is in 2007 there was about $518 million in IV iron sales in the U.S.,” she said, adding that the company has not given projections for ferumoxytol sales. If approved, the drug will be used for chronic kidney disease patients.

Most IV iron therapies are used by dialysis patients, who receive the treatment in infusions that often last hours. “Dialysis patients are in the chair three hours a day, three times a week, getting long infusions,” Galfetti said. Ferumoxytol, because of its unique carbohydrate coating, is administered by IV injection.

“What our product can offer is a half a gram of iron in a 17-second injection, which is a lot more convenient for patients and physicians,” Galfetti said. Ferumoxytol does not need refrigeration, has minimal immunological reactivity and a minimum of detectable free iron, she added.

Earlier this year, the company reported positive efficacy and safety results from four separate Phase III clinical trials of the drug (DID, April 7).

The company submitted its NDA in December 2007 and received the agency’s complete response letter requesting additional information last month. The FDA’s action regarding the company’s response is “definitely a step in the right direction,” Galfetti said, noting that if the agency had instead designated AMAG’s resubmission as a Class 2 response, the FDA would have had six months instead of two to make a decision.

AMAG will launch ferumoxytol in the first quarter of next year if the product is approved by Dec. 30, Galfetti told DID. — Elizabeth Collins


Orion Sues Sun Pharma to Protect Comtan

Finnish drugmaker Orion has filed a patent infringement suit against Sun Pharma Global, which submitted an ANDA to market a generic version of Comtan in 200-mg tablets to treat Parkinson’s disease.

The suit against Sun Pharma, a subsidiary of India’s Sun Pharmaceutical Industries based in the British Virgin Islands, was filed in the U.S. District Court for the District of New Jersey. Sun Pharma notified Orion and Novartis last month that it had filed an ANDA to market a generic version of Comtan (entacapone) before the drug’s ’194 patent expires Oct. 19, 2013.

Orion holds the NDA for the drug, and Novartis has an exclusive license to market it in the U.S.

However, generic competition for the drug is neither certain nor imminent. Orion and Novartis will vigorously defend the intellectual property rights associated with Comtan, Orion says in a statement.

Wockhardt also filed an ANDA for a generic version of Comtan last year and appears to have first-filer status. Orion’s patent infringement suit against Wockhardt is pending in the U.S. District Court for the District of Delaware. 

Orion and Sun are involved in separate litigation with each other over a generic version of Stalevo (carbidopa/levodopa/entacapone). That case also is pending in the U.S. District Court for the District of New Jersey. — Elizabeth Jones


ALS Drug Gets EMEA Orphan Designation

CytRx’s arimoclomol has received orphan drug designation from the European Medicines Agency (EMEA) to treat amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease.

ALS is a progressive disease in which nerve cells in the brain and spinal cord that control voluntary movement gradually deteriorate. To get the orphan drug designation for arimoclomol, CytRx had to prove to the EMEA’s satisfaction that it “might be of potential significant benefit” to patients, the agency says in a statement. The benefit must be confirmed when the drug gains EU marketing authorization.

Arimoclomol has orphan drug designation in the U.S. but has not received marketing approval. It works by stimulating production of “chaperone” proteins that help correct the misfolding of certain motor neuron proteins, according to the EMEA. Correcting the misfolding that is partly responsible for ALS alleviates symptoms of the disease.

CytRx says it is developing arimoclomol for other central nervous system disorders, including Alzheimer’s, Huntington’s and Parkinson’s diseases. In January, the FDA placed the company’s Phase II ALS clinical trial of the drug on hold pending additional data and preclinical toxicology studies.

In June 2007, the company reported promising data from a six-month open-label extension of its Phase IIa clinical trial of the drug in ALS volunteers.

Other drugs that recently received orphan designation from the EMEA are:

  • Analytica International’s autologous tumor-derived immunoglobulin idiotype coupled to keyhole limpet haemocyanin, which treats follicular lymphoma;
  • GP Pharm’s doxorubicin HCl, which treats soft-tissue sarcoma;
  • BCG Europe’s iodine (131I) anti-tenascin monoclonal antibody 81C6, which treats glioma, a type of brain tumor;
  • Apogenix’s recombinant fusion protein consisting of the extracellular portion of CD95 fused to the Fc part of a human IgG1 molecule, which prevents graft-versus-host disease; and
  • Orfagen’s tazarotene, which treats congenital ichthyoses.

The EMEA’s opinion on arimoclomol can be seen at www.emea.europa.eu/pdfs/human/comp/opinion/22572408en.pdf. The other orphan drug designation opinions can be accessed at www.emea.europa.eu/htms/human/orphans/opinions.htm. — Martin Gidron


AstraZeneca, Basilea Win Approvals in EU, Switzerland

EU regulators have expanded the indications for two formulations of AstraZeneca’s Seroquel to include its use for major depressive episodes in bipolar disorder.

Both Seroquel (quetiapine fumarate) and its extended-release (XR) version have been licensed for moderate-to-severe manic episodes in bipolar disorder. AstraZeneca will move to obtain local approvals with the 17 member states that take part in the EU’s mutual recognition procedure, according to a company statement.

The EU’s decision comes about a month after the FDA approved Seroquel XR for three new indications for bipolar disorder, bringing the product’s approved uses in line with those for the drug’s immediate-release formulation.

Seroquel XR previously had indications for acute schizophrenia and maintenance treatment of the disease. In bipolar disorder, it was approved for use as an acute treatment of depressive episodes. Seroquel also was approved for manic and mixed episodes associated with bipolar I disorder and as a maintenance treatment of bipolar I disorder as an adjunct to lithium or divalproex, according to a company statement (DID, Oct. 13).

The immediate-release version of the product is approved for schizophrenia and multiple indications in bipolar disorder conditions — including acute and maintenance indications.

Zevtera Approval

Separately, Swissmedic, the Swiss agency for therapeutic products, cleared Zevtera (ceftobiprole medocaril) to treat complicated skin and soft-tissue infections, including diabetic foot infections that have not spread to the bone.

Zevtera was developed through a collaboration between Swiss drugmaker Basilea Pharmaceutica and Janssen-Cilag, a Johnson & Johnson (J&J) company. Janssen will market the product in Switzerland.

The drug is under regulatory review in the U.S. and the EU. Subject to approval, Basilea will co-promote ceftobiprole in the U.S. and in major European markets with the respective J&J companies, Basilea says in a statement.

Health Canada granted marketing authorization to Zeftera, as the drug is spelled for that market, for skin and soft-tissue infections in June (DID, July 1).

Ceftobiprole has demonstrated broad-spectrum activity against many other gram-positive and gram-negative bacteria that are frequently associated with community and hospital-acquired infections. — Elizabeth Jones

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