First Year Of Marketing Research Articles

Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: a case/non-case study from the French Pharmacovigilance Database

In the recent past, concerns have raised regarding the potential risk of acute pancreatitis among type 2 diabetic patients using incretin-based drugs such as glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors. The aim of this study is to investigate the association between exposure to incretin-based drugs and the occurrence of pancreatitis reported in the French Pharmacovigilance Database. The case/non-case method was performed from serious adverse drug reactions(ADRs) involving antihyperglycemic agents (except insulin alone) reported to the French pharmacovigilance system between March 2008 (first marketing of an incretin-based drug in France) and March 2013. Cases were defined as reports of pancreatitis, and all other serious ADRs were considered non-cases. Disproportionality was assessed by calculating reporting odds ratios (ROR) adjusted for age, gender, history of pancreatitis, other antihyperglycemic drugs and other drugs associated with a higher risk of pancreatitis. Among 3,109 serious ADRs, 147 (4.7%) reports of pancreatitis were identified as cases and 2,962 reports (95.3%) of other ADRs as non-cases. Among the cases, 122 (83.0%) involved incretin-based drugs. Disproportionality was found for all incretin-based drugs (adjusted ROR: 15.7 [95% CI 9.8-24.9]), all GLP-1 analogs (29.4 [16.0-53.8]), exenatide (28.3 [12.8-62.3]), liraglutide (30.4 [15.4-60.0]), all DPP-4 inhibitors (12.1 [7.3-20.0]), sitagliptin (12.4 [7.3-21.0]), saxagliptin (15.1 [4.3-52.7]), and vildagliptin (7.4 [3.1-17.6]). Temporal analysis found disproportionality for incretin-based drugs since their first year of marketing in France. Compared with other antihyperglycemic agents, use of incretin-based drugs is associated with an increased risk of reported pancreatitis in France.

Ticlopidine-, Clopidogrel-, and Prasugrel-Associated Thrombotic Thrombocytopenic Purpura: A 20-Year Review from the Southern Network on Adverse Reactions (SONAR)

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Ticlopidine-, Clopidogrel-, and Prasugrel-Associated Thrombotic Thrombocytopenic Purpura: A Twenty Year Review

Abstract▪2226▪This icon denotes a clinically relevant abstract Objective:Thrombotic thrombocytopenic purpura (TTP) is a rare syndrome, with our group having identified the thienopyridines ticlopidine and clopidogrel as the most common drugs associated with TTP in Food and Drug Administration (FDA) databases. We review clinical, epidemiologic, laboratory, and drug safety findings for thienopyridine-associated TTP, including the first reported cases with prasugrel, a thienopyridine approved in 2009. Methods:Data sources included FDA’s Adverse Event Reports database, pharmaceutical manufacturers, package inserts, physician surveys, phase III reports, insurance databases, and an epidemiologic study (1989–2011). Causality was assessed with the World Health Organization scale. Results:Since 2002, FDA received reports of 10 ticlopidine-, 140 clopidogrel-, and nine prasugrel-associated TTP cases, including four, 11, and 9 cases respectively, in the first year of marketing of each agent. Surveys of hematologists by our group identified 32 ticlopidine- and ten clopidogrel-associated TTP cases. Thienopyridines were administered for > two weeks for 90% of 93 ticlopidine-associated cases, 26% of 35 cases clopidogrel-associated cases, and none of nine prasugrel-associated cases. In the Phase III setting, one of 2,932 ticlopidine-, none of 27,961 clopidogrel-, and none of 1,769 prasugrel-treated patients developed TTP. Insurance databases identified three clopidogrel-associated TTP case among 15.3 million individuals. Ticlopidine- (n=30) versus clopidogrel-associated TTP patients (n=8) presented with severe ADAMTS13-deficiency (80% versus 0%) and neutralizing auto-antibodies to ADAMTS13 (100% versus 0%) and had higher survival rates following therapeutic plasma exchange (87% versus 50%) (p<0.05). Greater than 95% of ticlopidine-associated TTP cases were assessed as having a probable causal relationship versus none of the clopidogrel- or prasugrel-associated TTP cases. TTP is described in a Black Box warning for ticlopidine (1998, incidence of 1 in 2,000) and as a warning for clopidogrel (2000; 12 per million) and prasugrel (2010; no incidence reported) Conclusion:TTP is associated with all thienopyridines, although causal relationships remain under active investigations. Disclosures:Armstrong:LeadHorse Technologies Inc.: Employment.

Utilization of the smoking cessation medicine varenicline: an intensive post‐marketing study in New Zealand

To examine the utilization of varenicline during the first year of marketing in New Zealand (NZ) and to examine how this compares with the dosing instructions recommended in the Champix product information. Dispensing records for all NZ patients prescribed varenicline were collected by the Intensive Medicines Monitoring Programme (IMMP) during the first year this medicine was available in this country. Analyses of these data included patient characteristics and patterns of usage-in particular the duration of treatment dispensed as the first course. An assessment of the effectiveness of varenicline in post-marketing use was also performed on a sub-group of the cohort for whom follow-up information was available. Of 3415 patients in the first year IMMP cohort, only 125 patients (4%) were dispensed the recommended 12 weeks varenicline treatment. 1299 (38%) were dispensed 14 days treatment (most often as a Starter Pack), 766 (22%) were dispensed 6 weeks, 411 (12%) were dispensed 4 weeks and 332 (8%) patients were dispensed more than 12 weeks treatment as a continuous course. The most common reasons for stopping varenicline prematurely were adverse reactions and cost of treatment. In a subgroup of 1299 patients, varenicline was reported to have been effective for 359 (28%) patients. In 'real-life' post-marketing use, most patients did not receive 12 weeks varenicline treatment as recommended in the Champix product information. This observation may have implications for the effectiveness of this smoking cessation medicine.

Enquête auprès des neurologues sur les prescriptions de natalizumab en région Provence-Alpes-Côte-d’Azur

Tysabri is indicated as single-drug disease-modifying therapy in patients with highly active relapsing remitting multiple sclerosis (RRMS). Potential risk for opportunistic infection and especially for progressive multifocal leucoencephalopathy has implied specific guidelines for use. The purpose of this study was to ascertain the prescription practices of neurologists in southern France and to learn more about how the drug is used in clinical practice compared with management guidelines stated in the product's characteristics and national recommendations. We developed a questionnaire which was sent to all neurologists practicing in our region, whether they had multiple sclerosis patients or not. Questions regarded demographic data (geography, practice in hospital or private office), current knowledge on natalizumab (mechanism of action, indications), monitoring of treated patients (pre-therapeutic and therapeutic check-up), rescue decisions and overall experience with using natalizumab. Two hundred fifty neurologists, practicing in eight administrative districts in our region, were contacted. Demographic data showed that most of them were prescribing Tysabri. Patients treated with Tysabri were mostly followed in teaching hospitals (79%). Concerning knowledge about natalizumab, neurologists applied the recommended check-up (73%) but most of them preferred prescribing Tysabri as a second line of treatment after IFN failure (66%). Inefficacy was mainly evaluated on clinical parameters (one or two relapses under treatment with sequels or EDSS progression in each answer); MRI was only useful to confirm clinical conclusions, but for the neurologists, gadolinium enhancement was required to confirm lack of efficacy. Results tended to show that, in clinical practice, despite some deviation from national guidelines, the recommended precautions are applied for the use of Tysabri. Neurologists considered that Tysabri is other immunosuppressant drugs used in RRMS. Further medical information might be useful to improve compliance with all of the recommended indications and standard practices for patient follow-up. This survey enabled an assessment of current knowledge about Tysabri as a treatment for RRMS patients and to learn more about how it was used in real life practice during its first year of marketing in France.

Incidence of spontaneous notifications of adverse reactions with aceclofenac, meloxicam, and rofecoxib during the first year after marketing in the United Kingdom

The objective was to compare the incidence of adverse reactions reported with three nonsteroidal anti-inflammatory drugs with different cyclo-oxygenase (COX)-2 selectivity. All spontaneous adverse reaction notifications in the pharmacovigilance database of the World Health Organisation Collaborating Centre for International Drug Monitoring with aceclofenac, meloxicam, and rofecoxib that were recorded during the first year of marketing were included. The incidence rate (adverse reactions/10(6) defined daily dose) and 95% confidence interval for total adverse reactions was 8.7 (6.1-12.0) for aceclofenac, 24.8 (23.1-26.6) for meloxicam, and 52.6 (49.9-55.4) for rofecoxib. Aceclofenac had a lower incidence of gastrointestinal bleeding, abdominal pain, and arterial hypertension than meloxicam and a lower incidence of gastrointestinal bleeding, abdominal pain, liver toxicity, thromboembolic cardiovascular events, arterial hypertension, and edema than rofecoxib. The incidence of total and gastrointestinal adverse reactions was significantly lower with aceclofenac than with meloxicam or rofecoxib, thus raising doubts about the hypothetical advantage of COX-2 selective inhibitors.

The Safety of Rosuvastatin as Used in Common Clinical Practice

Statins are currently the mainstay of dyslipidemia management for the primary and secondary prevention of cardiovascular disease. Controversial concerns about the safety of the newly marketed statin rosuvastatin have been raised on the basis of premarketing studies and a few postmarketing reports. We reviewed rosuvastatin-associated adverse events reported to the US Food and Drug Administration over its first year of marketing. On the basis of prescription data obtained from IMS Health, rates of adverse event reports (AERs) per million prescriptions were calculated. Rates of rosuvastatin-associated AERs over its first year of marketing were compared with those seen with atorvastatin, simvastatin, and pravastatin over the concurrent timeframe and during their respective first years of marketing. Comparison was also made to the first year of marketing of cerivastatin. The primary analysis examined the composite end point of AERs of rhabdomyolysis, proteinuria, nephropathy, or renal failure. With either timeframe comparison, rosuvastatin was significantly more likely to be associated with the composite end point of rhabdomyolysis, proteinuria, nephropathy, or renal failure AERs. Reported cases of rhabdomyolysis, proteinuria, or renal failure tended to occur early after the initiation of therapy and at relatively modest doses of rosuvastatin. The increased rate of rosuvastatin-associated AERs relative to other widely used statins was also observed in secondary analyses when other categories of AERs were examined, including adverse events with serious outcomes, liver toxicity, and muscle toxicity without rhabdomyolysis. The present analysis supports concerns about the relative safety of rosuvastatin at the range of doses used in common clinical practice in the general population.

Report card for accelerated FDA approval oncology drugs (1995- 2003): Is it time for a make-up test?

6002 Background: The FDA adopted accelerated approval in 1992 in order to improve access to new drugs based on studies that evaluated markers likely to predict clinical benefit. Methods: The performance of this program was assessed by reviewing new oncology licensing applications and supplements for new uses approved by the FDA from 1995 to September 2003. Data included: the application filing date for each agent, the date of approval, the types of studies that were assessed during FDA review, and the endpoints used in these studies. Results: Of the 21 oncologic indications which received accelerated FDA approval, subsequent studies that were required for conversion to regular approval were submitted and accepted (n=5) [capecitabine, dexrazoxane, docetaxiel, imitinab mesylate, irinotecan], submitted for regular approval but rejected by the FDA (n=3), or have not been submitted (n=14). Surrogate outcomes included response rate (n=16), symptom improvement (n=1) and reduced time to recurrence (n=1). Fourteen approvals were based on results of phase II clinical trials, while only 5 were based on phase III studies. Fewer than 200 patients were evaluated for efficacy for about 2/3 of the indications. Post-marketing studies identified potentially fatal adverse drug reactions for four of the drugs, three of which were identified within 7 months of initial FDA approval (capecitabine-associated interaction with warfarin, imatinib-associated hemorrhage in GIST, and gemtuzumab-associated VOD). Conclusions: To date, drugs which have received accelerated FDA approval have been frequently evaluated in small, short-term phase II clinical trials, have rarely been converted to regular FDA approval, and can have potentially fatal adverse drug reactions identified in the first year of marketing. No significant financial relationships to disclose.

The regenerative dialysis (REDY) sorbent system

SUMMARY: The concept of regenerating the spent hemodialysate instead of discarding it was first suggested by A. Johnson in 1966. Drs M. Maxwell and A. Gordon felt that development of the concept could provide information on uremic toxins and lead to a wearable artificial kidney. Suitable sorbents consisting of zirconium phosphate, hydrated zirconium oxide and carbon combined with urease were placed in a cartridge by Dr. L. Marantz. Uremic dogs were successfully maintained using this cartridge to regenerate the hemodialysate. After completion of human studies the system was placed on the market in 1973. Three major problems occurred in the first year of marketing: 1. Displacement of the urease by the liquid in the Cordis‐Dow dialysers. 2. Deafness after use with an unrinsed dialyser. 3. Inactivation of the urease by copper in the water supply. They were resolved by emptying the Cordis‐Dow dialyser, rinsing all dialyser before use and adding a scavenger layer to the cartridge. At first the major market for the REDY System was the home market. However, as this market shrank the major market became dialysis of the acute renal failure patient. After it was found that the eluant from the cartridge sometimes contained aluminium, the alumina in the zirconium layers was removed and the present cartridge no longed contributes aluminium to the dialysate but also can be used to remove aluminium from hemodialysate. Attempts have been made to use the system to develop a wearable kidney.

Evaluation of Gabapentin in an Outpatient and Office-based Sample of Epilepsy Patients

A retrospective analysis of charts of patients who received gabapentin (GBP) as adjunctive anticonvulsant therapy in its first year of marketing, between March 1994 and April 1995 was conducted to evaluate patterns of use, side effects, and efficacy in the general epilepsy population. Ninety patients (45 men, 45 women) with an average age of 33.5 years (range: 7 months–78 years) were included. Average GBP dosage was 1700 mg/day; 46 patients took <1800 mg, and 44 patients took ⩾1800 mg/day. Duration of GBP treatment ranged from 1 month–14 months. Patients took an average of 1.7 concurrent antiepileptic drugs while on GBP. A total of 13 patients were on GBP monotherapy, four at the outset joined by nine others during the study. Gabapentin was associated with improvement as assessed by reduction of seizure frequency in 69 patients (77%). Sixty patients (67%) who reported no side effects had a mean GBP dosage of 1900 mg/day (median: 2000 mg/day). The 30 patients who experienced side effects had a mean GBP dosage of 1600 mg/day (median: 1500 mg/day). Gabapentin was discontinued in 21 patients, six because of side effects, nine because of lack of efficacy, and six because of a combination of both. Gabapentin was used in more difficult patients with intractable epilepsy and was generally well tolerated. Higher doses were not associated with more side effects, suggesting that GBP-related side effects may not be dose-related.

Myopathy and Rhabdomyolysis Associated With Lovastatin-Gemfibrozil Combination Therapy

The Food and Drug Administration documents the receipt of 12 case reports of severe myopathy or rhabdomyolysis associated with concomitant use of lovastatin and gemfibrozil, including 10 voluntary postmarketing, and 2 required, reports. All patients had serum creatine kinase levels of more than 10,000 U/L, 4 tested showed myoglobinuria, and 5 had acute renal failure. The patients' symptoms resolved when both drugs were discontinued. For the first year of marketing of lovastatin, spontaneous reports of myopathy with documentation of creatine kinase level were reviewed for the use of lovastatin, gemfibrozil, and combination therapy. The median creatine kinase level in reports involving concomitant lovastatin and gemfibrozil use was 15,250 U/L, 20 times that in reports with gemfibrozil use alone and 30 times that in reports with lovastatin use alone. Because of the potential for severe myopathy and life-threatening rhabdomyolysis, and given alternative drug combinations for treating hyperlipoproteinemia, the use of lovastatin in combination with gemfibrozil is to be discouraged.

Adverse Reactions Reported Following Receipt of Haemophilus influenzae Type b Vaccine: An Analysis After 1 Year of Marketing

An analysis of adverse reactions occurring after receipt of Haemophilus influenzae type b vaccine and reported to the Food and Drug Administration during the first year of marketing of the product was performed. During the period April 1985 to May 1986, adverse reaction reports on 152 patients, excluding those of vaccine failure and concurrent infection, were received. Several adverse reactions not previously recognized, including convulsions, allergic reactions such as anaphylactoid-like and serum sickness-like reactions, and vomiting were received. The vast majority of adverse reactions were benign. Because there are many biases that result in the reporting of or failure to report an adverse reaction, it is not possible to derive a rate of reactions from these data. Furthermore, causality cannot be inferred from any single report. The data, however, indicate that, in light of widespread use of the vaccine, its use appears to be safe.

SAFETY OF HAEMOPHILUS INFLUENZAE TYPE b VACCINE.

In 1985, the Haemophilus influenzae type b vaccine was licensed for children two to five years of age; more than 4.5 million doses were sold in the first year of marketing. Milstien and colleagues …

Evaluation of adverse reaction reports for a newly laundry product.

The marketing of widely used consumer products inevitably results in some reports of adverse dermatologic reactions which are tentatively attributable through medical history to the use of these products. Just as it is important for manufacturers to perform thorough premarket safety testing, it also is important for them to investigate these reported reactions to confirm the safety of the product under widespread use conditions. This report describes the results of such a follow-up investigation into 300 adverse reaction reports obtained during the first year of marketing of new laundry product. The results of diagnostic patch and prick tests, controlled reuse testing, and definitive diagnoses by physicians (mostly allergists and dermatologists) demonstrated that this product was highly unlikely to have caused the reported dermatologic conditions. Widespread distribution of free samples of the new product appeared to be largely responsible for the frequency of anecdotal association of adverse reactions to use of the product. The diagnostic follow-up program is described.