Drug Information Bulletin (Electronic)

Drug Information Centre (DIC) Indian Pharmaceutical Association, Bengal Branch Tele fax: 033 24612776, E-mail: ipabengal.dic@gmail.com Web Site: http://www.ipabengal.org Contact: 09830136291

Volume: 4 2011

Number: 44

13th February

Content
New Drug: Certolizumab Thirteen states seek federal aid to obtain Sodium Thiopental Many breakthrough research Medications, Vaccines come from publicly funded

USP launches drug quality programme in sub-Saharan Africa Natco Pharma challenging Gilead's Flu treatment Patent Ayush Dept. still trying to delay proposed EU ban on ayurvedic drugs

New Drug: Certolizumab Certolizumab, like adalimumab, etanercept and infliximab, is a tumour necrosis factor inhibitor indicated for rheumatoid arthritis. It is a recombinant humanised antibody Fab' fragment which has been pegylated to extend its plasma half-life to that of the whole antibody. Peak plasma concentrations are reached between 54 and 171 hours after subcutaneous administration and its bioavailability is approximately 80%. The terminal elimination half-life is around 14 days. However, the presence of antibodies to certolizumab increases its clearance and appears to correlate with reduced patient responses. Giving methotrexate concomitantly with certolizumab reduces the formation of anti-certolizumab antibodies.

Certolizumab is indicated for adults with moderate to severely active rheumatoid arthritis. It should be combined with methotrexate in patients who have had an inadequate response to or are intolerant to other treatments with one or more disease-modifying antirheumatic drugs. Certolizumab should only be given on its own if methotrexate is contraindicated or not tolerated. The efficacy of certolizumab has been studied in three placebo-controlled phase III trials. One of the studies was in 982 patients with active rheumatoid arthritis who had not responded to methotrexate therapy alone. Fortnightly certolizumab (three initial 400 mg doses followed by a maintenance dose of 200 mg or 400 mg given subcutaneously) or placebo was added to methotrexate

treatment. (For this trial, certolizumab was reconstituted from lyophilised powder.) Patients' response to therapy was measured over 52 weeks according to the American College of Rheumatology 20% (ACR20) criteria for improvement. This is a composite outcome based on the number of swollen and tender joints, the erythrocyte sedimentation rate or Creactive protein concentration and global assessments of arthritis activity by the patient and doctor. Joint damage was also assessed by radiology using a modified Sharp score. Certolizumab significantly reduced the signs and symptoms of rheumatoid arthritis compared to placebo. After 24 weeks, 58.8% and 60.8% of patients receiving 200 mg and 400 mg of certolizumab had an ACR20 response compared to 13.6% in the placebo group. Progression of joint damage was significantly less with certolizumab than with placebo - at week 52, mean changes in the Sharp score from baseline were 0.4 units for certolizumab 200 mg, 0.2 units for certolizumab 400 mg and 2.8 units with placebo. The higher certolizumab dose did not seem to offer any additional clinical benefit over the lower dose. In the trial, adverse events were comparable between groups with headache, hypertension and back pain being the most common non-infectious events. However, headache was more common with placebo (12% of patients) and hypertension was more common with certolizumab (9.2% of patients). Seven patients died while receiving treatment one in the placebo group (cardiac arrest) and six in the certolizumab groups (hepatic neoplasm and cardiac arrest with 200 mg dose and stroke, cardiac arrest, atrial fibrillation and fatigue, and myocardial necrosis with 400 mg dose). Twelve patients

2 receiving certolizumab withdrew because of infection. There were no withdrawals due to infection in the placebo group. Serious infections included lower respiratory tract infections, gastroenteritis, urinary tract infections and tuberculosis. Malignancies were found in 12 patients 1/199 receiving placebo and 11/781 receiving certolizumab. At week 52, 6.4% of patients receiving certolizumab had antibodies to the study drug. Another phase III trial (619 patients) with a similar design, but using liquid certolizumab, showed similar rates of efficacy in rheumatoid arthritis after 24 weeks of treatment (ACR20 rates: 5758% with certolizumab vs 9% with placebo). Serious infections occurred with certolizumab but not with placebo (3.2% and 2.4% of patients receiving certolizumab 200 mg and 400 mg vs 0% receiving placebo). Infections included tuberculosis, gastroenteritis, skin infections, postoperative wound infection, tooth abscess, urosepsis, pneumonia, upper respiratory tract infection and sinusitis. There was one case of lupus erythematosus rash with certolizumab 200 mg. Certolizumab without methotrexate has been assessed in a trial of 220 patients who received either certolizumab 400 mg or placebo every four weeks. After 24 weeks, 45.5% of patients receiving monotherapy had responded (ACR20) compared to only 9.3% of patients receiving placebo. Adverse effects were seen in 75.6% (84 of 111) of the people in the certolizumab group versus 57.8% (63 of 109) in the placebo group. These were mostly mild or moderate but there were three serious events with placebo (vomiting, chronic renal failure, pneumonitis) and eight with certolizumab (aggravated rheumatoid arthritis (two cases), bacterial arthritis,

mastitis, benign parathyroid tumour, postural dizziness, ischaemic stroke and uterine bleeding). An open-label extension study in 402 patients indicated that the benefits of certolizumab (with or without methotrexate) may not be sustained over prolonged periods (up to 112 weeks) in some people. The presence of anti-certolizumab antibodies seemed to reduce the likelihood of maintaining a response to treatment. As certolizumab modulates the immune system there is a risk of serious infection. It is contraindicated in active tuberculosis and other serious infections such as sepsis or opportunistic infections. Patients should be tested for active or latent tuberculosis before and during treatment. Reactivation of hepatitis B virus has been reported with certolizumab so carriers should be closely monitored for active infection. Once treatment is stopped, elimination of certolizumab may take five months, so monitoring should be continued for this period. Caution is also urged when considering certolizumab for patients with a history of cancer or demyelinating disorders. This drug is contraindicated in patients with moderate to severe congestive heart failure. It should not be used in combination with anakinra or abatacept. Live or attenuated vaccines should not be given with certolizumab and it should not be used in pregnancy. Certolizumab offers an alternative to patients who have not responded to other rheumatoid arthritis treatments. About two-thirds of patients in the trials responded to certolizumab when it was added to methotrexate. Certolizumab also showed some efficacy when given as a monotherapy although response

3 rates were 10-20% lower without methotrexate. It is not known how certolizumab will compare to the other tumour necrosis factor inhibitors as there have been no comparative trials so far.
Source: Aust Prescr 2010; 33:129-131

Thirteen states seek federal aid to obtain Sodium Thiopental AFP reports, "The US Department of Justice said it was reviewing a request from 13 states asking for help in obtaining a drug used for executions that is no longer manufactured in the US." The request came from the attorneys general of Alabama, Colorado, Delaware, Florida, Idaho, Mississippi, Missouri, Nevada, Oregon, Tennessee, Utah, Washington and Wyoming. "The last doses of thiopental made in the US will reach expiration this spring, which will put the 35 US states that practice the death penalty at a crossroads." The only drugmaker, Hospira, authorized by the Food and Drug Administration to produce sodium thiopental "on US soil" announced Jan. 21 that it "has permanently stopped production." Medicines Patent Pool in Negotiation with Key HIV/AIDS Medicines Patent Holders On 1 December 2010, the Medicines Patent Pool sent out letters to key patent holders inviting them to formally begin negotiations to license their HIV/medicines patents to the Pool, and requesting a reply by January 31, 2011. The Pool has now received responses from all of the patent holders. F. Hoffman-La Roche, Gilead Sciences, Sequoia Pharmaceuticals, and ViiV Healthcare (a joint venture of GlaxoSmithKline and Pfizer) have taken the lead and have entered or are preparing to enter into active negotiations with the Pool. The Pool

received its first licence in September 2010 from the US National Institutes of Health (NIH), and is in ongoing discussions regarding further licensing opportunities with the NIH. At the same time, the Pool is encouraged that some patent-holders have begun adopting 'policies supported by the Pool, such as increased adoption of voluntary licensing, including for pipeline products still in development. The Pool looks forward to continuing to dialogue with all relevant patent holders to achieve the goal of increasing access to medicines for people living with HIV in developing countries. This represents great progress in pioneering a model that works for companies and for patients who need access to new and better medicines. But we need other patent holders to engage with the Pool too. It is only through conversation that we can work through differences and achieve critical public health goals, said Ellen t Hoen, executive director of the Medicines Patent Pool. A table summarising the current status of engagement with patent holders, and additional information (including the responses from companies) has just been made live on our website here: http://www.medicinespatentpool.org/LIC ENSING/Company-Engagement
Source:Ip-health

4 England Journal of Medicine. Study author Ashley J. Stevens, a lecturer at the Boston University School of Medicine and senior research associate at the university's Institute of Technology Entrepreneurship and Commercialization, and colleagues, "count 153 new drugs and vaccines from public sector research institutes over the past 40 years." The 153 "entities identified by the authors included 93 small-molecule drugs, 36 biological agents, 15 vaccines, eight diagnostic tools and one over-thecounter drug." USP launches drug quality programme in sub-Saharan Africa The United States Pharmacopeoia (USP) will help regulators in subSaharan Africa ensure drug quality in a new scheme designed to boost testing and analysis capacity. The technical assistance programme (TAP) will provide agencies in Ethiopia, Ghana, Kenya, Senegal and Sierra Leone with anything from reference standards to technical documents and training as USP spokesperson Laura Provan explained. Official medicines control groups in each country will decide what reference and documentary standards in the USPNF best meet their needs. While we expect that drugs for infectious diseases such as malaria, TB, and HIV/AIDS, as well as antibiotics, will be frequently requested, USP will not limit access to standards. And, she continued, while Government agencies will be the main focus the USP may also work with any local contractors if a government had contracted with an organization to help them in medicines quality control.

Many breakthrough Medications, Vaccines come from publicly funded research HealthDay reported, "A surprising number of valuable new drugs and vaccines approved in the United States have arisen wholly from research funded by the public sector," according to a study published Feb. 10 in the New

The success of the 12-month pilot scheme will be assessed using metrics ranging from straightforward quality assessments and counterfeit detection levels to more complex factors like improved access to medicines. PQM expansion The TAP is an expansion of the USPs promoting the quality of medicines programme (PQM), which is focused on the identification and removal of substandard and counterfeit medicines from various markets worldwide. The PQM is already established in four of the five countries covered by the TAP, which was an important factor in choosing to launch the programme in this region according to Provan. We felt that in a pilot program it would be best to work with people and organizations who were familiar with USP and our local staff, she explained, adding that regulators in the one non PQM country, Sierra Leone, had asked to take part. And, she continued, if TAP is successful the USP may launch the scheme elsewhere in 2011, adding that: The USP is already in discussions with Egypt, India, and several of the less developed ASEAN countries. TAP into emerging markets In addition to its obvious benefits for public health, the TAP pilot is also likely to benefit USP as it will further establish the organisation as the leading pharmaceutical quality and standards body, particularly in increasingly important new markets as Provan explained. More than half our sales of standards come from outside the US and most of that is from countries like India and China that are the pre-eminent

5 suppliers of drugs and ingredients to emerging markets.

Source: in-Pharma Technologist.com

Natco Pharma challenging Gilead's Flu treatment Patent The AP reported, Gilead Sciences "said Monday that Natco Pharma Ltd. is challenging a patent on the flu drug Tamiflu (oseltamivir phosphate)." Natco, which is seeking FDA approval to sell a generic version of Tamiflu, "alleges that Gilead's patent on the drug is invalid." Gilead said it is "reviewing the notice it received from the FDA and has 45 days to file a lawsuit against Natco." Ayush Dept. still trying to delay proposed EU ban on ayurvedic drugs Though almost lost the case so far, the Department of Ayush claimed that it was still working intensely to delay and dissuade the European Union Directorate from going ahead with the ban on the sale of Indian ayurvedic and other herbal medicines across Europe from May 1. The Department, while continuing the talks with EU and writing to them on the quality of Indian medicines, has also sought the assistance of the Commerce Department to press the case of the country. It has taken up the matter with Commerce Ministry to push the issue through World Trade Organisation as it is another kind of trade barrier, sources said. After 4 years of debate with the European Commission over the THMPD, the Indian Government has made little headway. They are still going ahead with the full implementation of the directive. This legislation is not of scientific nature, but of trade and political nature. Still we are trying if we

can at least extend this transition period, a senior official of the department responded on the issue. The Traditional Herbal Medicine Product Directive (THMPD) by the EU came into force in 2004, but has given a transition period till April 30, 2011. Under the directive, a company needs to demonstrate the safety and efficacy of the herbal medicine through traditional use within the EU for at least 30 years or 15 years within the EU and 30 years outside the EU. The THMPD was intended to provide a simplified registration process for traditional herbal medicines sold Over the Counter (OTC), rather than following consultation with a practitioner. Since the Directive came into force in 2004, a not a single herbal medicinal product associated with any of the diverse non-European traditional medicine systems, such as Ayurveda, Traditional Chinese Medicine (TCM) or Tibetan medicine, has been registered under the scheme. When the 7-year transition period ends on 30 April 2011, all unregistered products will become illegal, said the official of the Ayush department. Forthcoming events

IPA Presidents National Seminar on Regulatory Challenges Global Pharmaceutical Market

5th March, 2011, Hotel Grand Kakatiya, Hyderabad, India

Organized by: Indian Pharmaceutical Association Registration & other details: