Swedish Medical Products Agency Research Articles

Treatment of HIV infection: Swedish recommendations 2009

On 4 previous occasions, in 2002, 2003, 2005 and 2007, the Swedish Medical Products Agency (Läkemedelsverket) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly published recommendations for the treatment of HIV infection. In November 2008, an expert group under the guidance of RAV once more revised the guidelines, of which this is a translation into English. The most important updates in the present guidelines include the following: (a) treatment initiation is now recommended at a CD4 cell count of approximately 350/microl; (b) new recommendations for first-line therapy: abacavir/lamivudine or tenofovir/emtricitabine in combination with efavirenz or a boosted protease inhibitor (PI/r); (c) an increased focus on reducing the use of antiretroviral drugs that may cause lipoatrophy; (d) an emphasis on quality assurance of HIV care through the use of InfCare HIV; (e) considerably altered recommendations for the initiation of antiretroviral therapy in children. All infants (<1 y) should start antiretroviral therapy, regardless of immune status. Also, absolute CD4+ cell counts, rather than percentage, may be used to guide treatment initiation in children above the age of 5 y.

Data Mining in Pharmacovigilance – Detecting the Unexpected

One of the most important aims of pharmacovigilance is to detect signals of adverse drug reactions (ADRs) as early as possible. However, some ADRs are difficult to detect, one example being so called 'type C' reactions. These are effects that present as seemingly 'spontaneous' diseases occurring during treatment with a drug, such as the occurrence of a cardiovascular event while the patient is taking rofecoxib. As this type of ADR is often mistaken for a spontaneous disease, the causative agent may appear as an innocent bystander. The primary aim of this study was to investigate the possibility of using data mining approaches to detect signals of 'type C' reactions. We hypothesized that by including concomitant, and not only suspected medications in the calculations of disproportionality analyses, we would be able to identify such reactions. We used data from the Swedish Drug Information System, SWEDIS, which contains spontaneous reports submitted by Swedish physicians to the Swedish Medical Products Agency, and applied Bayesian confidence propagation neural network (BCPNN) methodology to calculate the information component (IC) value for drug-event combinations for drugs belonging to the Anatomic Therapeutic Chemical (ATC) classes cardiovascular system, musculoskeletal system and nervous system (number of reports = 51 270) where only the suspected drug was considered, and also where both concomitant and suspected drugs were considered. We then classified drug-event combinations that were signalled by a statistically significantly raised IC value as labelled or unlabelled based on the approved summary of product characteristics (SPC) in Sweden as of November 2007, and further classified them as 'type C' reactions or not 'type C'. The proportion of 'type C' reactions signalled when considering both concomitant and suspected drugs compared with suspected drugs only. The proportion of labelled drug-event combinations when considering suspected drugs was 78.6%. Drug-event combinations classified as 'type C' reactions were more likely to be found when considering both concomitant and suspected drugs compared with suspected drugs only; 18/449 versus 0/248 when considering drug-event combinations that were signalled exclusively by one of the approaches. Such drug-event combinations included, for example, sudden death and celecoxib, myocardial infarction and diclofenac, suicide-related events and several antidepressants. Including both concomitant and suspected drugs in data mining practices may be a way of detecting 'type C' reactions earlier. This could constitute an advance in data mining for pharmacovigilance practices.

The Swedish Medical Products Agency has received 465 reports of renal adverse reactions associated with drugs affecting the renin-angiotension-aldosterone system.

The Swedish Medical Products Agency has received 465 reports of renal adverse reactions associated with drugs affecting the renin-angiotension-aldosterone system.

The Swedish Medical Products Agency has received 465 reports of renal adverse reactions associated with drugs affecting the renin-angiotension-aldosterone system.

The Swedish Medical Products Agency has received 465 reports of renal adverse reactions associated with drugs affecting the renin-angiotension-aldosterone system.

Prophylaxis and treatment of HIV-1 infection in pregnancy: Swedish Recommendations 2007

Prophylaxis and treatment with antiretroviral drugs, a consequent low viral load, and the use of elective Caesarean section, are factors that radically decrease the risk of HIV transmission from mother to child during pregnancy and delivery. The availability of new antiretroviral drugs, updated general treatment guidelines and increasing knowledge of the importance of drug resistance, have necessitated recurrent revisions of the recommendations for 'Prophylaxis and treatment of HIV-1 infection in pregnancy'. For these reasons, The Swedish Reference Group for Antiviral Therapy (RAV) has, at an expert meeting on May 4, 2007, once more updated the treatment recommendations of 1999, 2002 and 2005, which were defined in cooperation with the Swedish Medical Products Agency (Läkemedelsverket). This new text takes the recently updated general HIV treatment recommendations into account. Furthermore, the very low risk of HIV transmission when the mother is treated with combination antiretroviral therapy, has undetectable levels of viraemia and no obstetric risk factors, has been considered in the recommendations concerning the mode of delivery. Finally, the recommendations for monitoring of infants born to HIV-infected mothers have been modified. The recommendations are evidence graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels).

Venous Thromboembolic Events in Women Using the NuvaRing®.

Venous thromboembolic events (VTEs) are serious adverse effects seen in some women using oral contraceptives. Although the novel vaginal ring, (NuvaRing®) has been reported to be effective and well tolerated, the risks of VTEs are unknown. We report 3 women who developed potentially life-threatening VTEs (2 with pulmonary emboli and 1 inferior vena cava thrombus) while on the NuvaRing®. VTEs occurred 22 days, 3 months and 3 months after NuvaRing® insertion. None had a personal or family history of VTEs. Extensive thrombophilia evaluation showed 1 with heterozygous factor V Leiden and 2 with a transient lupus anticoagulant. 2 had a personal history of multiple miscarriages and all 3 had an elevated body mass index &gt; 26. Searching Pubmed, Ovid and Medline, there have been 10 other reported cases of VTEs, in women using the vaginal ring (see table below). Risk factors reported by other authors include anticardiolipin antibodies, protein S deficiency, heterozygous prothrombin 20210, heterozygous factor V Leiden and prolonged air travel. With limited follow up, the true incidence of VTEs in women using the NuvaRing® is difficult to determine. However, in 2005 the Swedish Medical Products Agency reported a relative incidence of 5.3 cases per 10,000 women years for VTE complications. In summary, we report 3 women who had life-threatening VTEs associated with the use of the NuvaRing®. Longer follow-up of safety studies and post-marketing adverse event reporting are needed to determine VTE risks and incidence while using the NuvaRing®. Studies reporting VTEs in women using the NuvaRing® Source Number of patients VTE risk factors Family history Site Bjarnadottir et al, 2002 1/121 Unknown Unknown LE DVT Tuppurainen el al, 2004 1/40 Unknown Unknown LE DVT Oddsson et al, 2005 1/512 Unknown Unknown LE DVT Miller et al, 2005 1/429 Anticardiolipin antibodies, protein S deficiency Grandmother with DVT LE DVT Ahrendt et al, 2006 1/499 Double heterozygous factor V Leiden/prothrombin 20210, prolonged air travel Unknown LE DVT Roumen et al, 2006 1/854 Unknown Unknown Cerebral sinus thrombosis Samuelsson et al, 2007 1 Heterozygous prothrombin 20210 None Axillary vein DVT Swedish Medical Products Agency, 2005 4/? Unknown Unknown DVTs Shum et al, 2007 3 Obesity (3), Personal history of miscarriages (2), heterozygous factor V Leiden (1) 1 sister with miscarriage Bilateral pulmonary emboli (2), Iliac vein-IVC thrombus (1)

Health economic evaluations alongside clinical trials: A review of study protocols at the Swedish Medical Products Agency

Conducting economic evaluation in the context of clinical studies is common but has been the subject of extensive discussion due to its limitations. Various standard approaches and guidelines how such studies should be conducted have been proposed, but there is very limited information available about how common these studies are, what type of data that is collected, and how the quality of the protocols compares to the suggested standards. This study examines the prevalence and study design of health economic evaluations conducted alongside clinical trials in Sweden between 1995 and 2005. A systematic assessment of clinical trial protocols that had arrived as applications to the Medical Products Agency between 1995 and 2005 was performed. Only protocols arriving during the first half of odd years within the time period were included. A total number of 680 protocols from 1995 to 2005 were examined, and among them, 14.4 percent included a health economic part. With the exception of year 2001, a trend toward an increased prevalence of economic evaluations next to clinical trials can be seen. This study shows that economic evaluations alongside clinical trials are becoming more common, although most trials still lack a health economic part of the protocol. The information about the economic evaluation provided in the protocols is in many cases scarce, possibly due to the fact that there currently are no generally accepted and applied guidelines for economic evaluations in clinical trial protocols. Introducing requirements for detailed study plans also for the economic evaluation should improve the quality of economic evaluations alongside clinical trials.

Adverse effects by artificial grapefruit seed extract products in patients on warfarin therapy

Grapefruit seed extract (GSE) is promoted as a natural product with antibacterial and antiviral properties. The aim of this study was to investigate the composition of some commercially available GSE products and evaluate their effect in vitro on two cytochrome P450 enzymes, CYP2C9 and CYP3A4. A couple on lifelong treatment with warfarin and continuous regular follow-ups took some drops of a GSE product for 3 days. The female patient experienced a minor subcutaneous haematoma 3 days later, and her international normalised ratio (INR) value was 7.9. This was reported to the Swedish Medical Products Agency (MPA) as a spontaneous post-marketing report concerning adverse drug reactions/interactions. The composition of the GSE products was determined by proton and carbon-13 nuclear magnetic resonance spectroscopy (NMR). The inhibitory effect of the GSE products on the cytochrome P450 enzymes was tested in an in vitro baculosome assay. The NMR analysis showed that all three investigated GSE products contained the synthetic preservative benzethonium chloride (BTC) in addition to glycerol and water. No authentic GSE extract was found in any of the three GSE products analysed. Furthermore, BTC was found to be a potent inhibitor of CYP3A4 and CYP2C9 activity in vitro. Our results suggest that BTC in the GSE products is responsible for the increase in the INR value in a patient on warfarin treatment.

Antiretroviral treatment of HIV infection: Swedish recommendations 2007

On 3 previous occasions, in 2002, 2003 and 2005, the Swedish Medical Products Agency (Läkemedelsverket) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly published recommendations for the treatment of HIV infection. An expert group, under the guidance of RAV, has now revised the text again. Since the publication of the previous treatment recommendations, 1 new drug for the treatment of HIV has been approved - the protease inhibitor (PI) darunavir (Prezista). Furthermore, 3 new drugs have become available: the integrase inhibitor raltegravir (MK-0518), the CCR5-inhibitor maraviroc (Celsentri), both of which have novel mechanisms of action, and the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (TMC-125). The new guidelines differ from the previous ones in several respects. The most important of these are that abacavir is now preferred to tenofovir and zidovudine, as a first line drug in treatment-naïve patients, and that initiation of antiretroviral treatment is now recommended before the CD4 cell count falls below 250/microl, rather than 200/microl. Furthermore, recommendations on the treatment of HIV infection in children have been added to the document. As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels).

Antiretroviral treatment of HIV infection: Swedish recommendations 2005

On 2 earlier occasions, in 2002 and 2003, the Swedish Medical Products Agency (MPA) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly publicized recommendations for the treatment of HIV infection. A working group from the same expert team that produced the 2002 report has now revised the text again. Since the publication of the last treatment recommendations, 4 new medicines have become available: emtricitabine, atazanavir, fosamprenavir, and enfuvirtid. The last-mentioned belongs to a new class of HIV medications called fusion inhibitors (Box 1). It is likely that tipranavir will also be on the market soon. Simultaneously, the drug zalcitabin has been deregistered. The following updated recommendations parallel the earlier ones, but increased knowledge allows us to be more specific in our recommendations. Thus, it is now suggested that the initial treatment for HIV infection consist of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 non-nucleoside reverse transcriptase inhibitor (NNRTI); or 2 NRTIs and 1 protease inhibitor (PI). In the group of the NRTIs, stavudine is no longer recommended for this purpose. In the NNRTI group, efavirenz should be preferred to nevirapine, except under special circumstances. Finally, PIs ought to be boosted with ritonavir (PI/r). Also new are recommendations regarding treatment choices for patients co-infected with hepatitis B virus (HBV) or tuberculosis (TB). As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels), and have been supplemented with references to newly-added sections and data not referred to in earlier background documentation.

Are pharmaceuticals potent environmental pollutants?: Part II: Environmental risk assessments of selected pharmaceutical excipients

As part of achieving national environmental goals, the Swedish Government commissioned a report from the Swedish Medical Products Agency on environmental effects of pharmaceuticals and cosmetics and hygiene products. Five excipients used in pharmaceutical products were selected for environmental risk assessments, applying the computer-based model EUSES. Docusate sodium was identified as a possible risk for sediment-dwelling organisms when taking the total amount used into account. Although, experimental toxicity data on sediment-dwelling organism and data on concentrations in sediments are still required before firm conclusions regarding the environmental risk can be made. The environmental risks posed by excipients used in pharmaceutical products are likely to be negligible. This study identifies that knowledge gaps regarding environmental risks posed by pharmaceutical excipients are evident.

Are pharmaceuticals potent environmental pollutants?: Part I: Environmental risk assessments of selected active pharmaceutical ingredients

As part of achieving national environmental goals, the Swedish Government commissioned an official report from the Swedish Medical Products Agency on environmental effects of pharmaceuticals. Considering half-lives/biodegradability, environmental occurrence, and Swedish sales statistics, 27 active pharmaceutical ingredients were selected for environmental hazard and risk assessments. Although there were large data gaps for many of the compounds, nine ingredients were identified as dangerous for the aquatic environment. Only the sex hormones oestradiol and ethinyloestradiol were considered to be associated with possible aquatic environmental risks. We conclude that risk for acute toxic effects in the environment with the current use of active pharmaceutical ingredients is unlikely. Chronic environmental toxic effects, however, cannot be excluded due to lack of chronic ecotoxicity data. Measures to reduce potential environmental impact posed by pharmaceutical products must be based on knowledge on chronic ecotoxic effects of both active pharmaceutical ingredients as well as excipients. We believe that the impact pharmaceuticals have on the environment should be further studied and be given greater attention such that informed assessments of hazards as well as risks can be done.

Paediatric adverse drug reactions reported in Sweden from 1987 to 2001

To describe frequency, seriousness and recovery of the patient in reported suspected paediatric adverse drug reactions (ADRs) in Sweden using data from a nation-wide ADR reporting system. Data from ADR reports submitted to the Swedish Medical Products Agency (MPA) were collected from the database SWEDIS and analysed for the period from 1987 to 2001. All reports with certain, probable or possible causality assessments referring to paediatric patients < 16 years of age were included. In 5771 children an ADR report was documented during the whole 15-year period in a paediatric population of about 1.7 million individuals. The annual reporting frequency was about 385 reports per year. The most frequently reported reactions were application site reaction (24%) followed by fever (12%) and exanthema (6.7%). The clearly most frequently reported group of drugs were the vaccines (63.8%) followed by antibiotics for systemic use (10.1%). The proportion of children that suffered from a serious ADR was 13.0% and that for drug related deaths 0.14%. Nine per cent of the children had not recovered at the time of reporting and 1% recovered with sequelae. A male overrepresentation was observed regarding the total number of reports. About two-third of the reports concerned outpatients less than 4 years of age. In respect of the limited number of paediatric drug safety studies or availability of record-linkage databases, nation-wide reporting systems of ADRs represent a valuable hypothesis generating tool in evaluating the characteristics of ADRs occurring in the orphan paediatric population.

Risk for fatal statin‐induced rhabdomyolysis as a consequence of misinterpretation of ‘evidence‐based medicine’

Journal of Internal MedicineVolume 257, Issue 3 p. 313-314 Free Access Risk for fatal statin-induced rhabdomyolysis as a consequence of misinterpretation of ‘evidence-based medicine’ First published: 16 February 2005 https://doi.org/10.1111/j.1365-2796.2005.01453.xCitations: 7 Mats Eriksson, Centre for Metabolism and Endocrinology, Department of Medicine, Karolinska University Hospital, 141 86 Huddinge, Sweden. (fax: +8 585 82407; e-mail: mats.eriksson@medhs.ki.se). AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Dear Sir, Statin treatment is an enormous progress in the treatment of atherosclerosis. The careful institution of such therapy in large numbers of patients at increased risk for coronary death represents a great challenge both to practising physicians and to the funding bodies of health care. In order to ensure appropriate treatment at low cost there is presently a trend to recommend statin treatment at a fixed dose regardless of initial lipid values and without evaluating therapeutic effects such as cholesterol levels. Evidence of such measures is mainly based on the data published from the MRC/BHF Heart Protection Study (HPS) where 40 mg simvastatin was used as a fixed dose [1]. Further, from July 2004, simvastatin is available without prescription in the UK [2]. We recently observed two cases of severe rhabdomyolysis caused by simvastatin treatment initiated based on regional recommendations. One of them was an 80-year-old female with a history of myocardial infarctions, kidney insufficiency, myocardial infarctions and heart insufficiency. She was given 40 mg of simvastatin promptly after a myocardial infarction, and was readmitted 6 months later because of weakness and severe muscle pain. Myoglobin level was above 3000 μL−1 and she died of multiple organ insufficiency after a month. Our opinion is that 40 mg simvastatin was the causative agent for this severe rhabdomyolysis and death. In the HPS [1] study, a very low frequency of side-effects was seen and there was no statistical difference between the treatment group (40 mg simvastatin) and the placebo group regarding myopathy or creatinine kinase (CK) elevations. At the end of the study compliance was 85% in the simvastatin group (n = 8590). However, in the placebo group 17% took a non-study statin (n = 1715). There is no mention of whether those who developed myopathy in the placebo group were those taking a non-study statin. If so, there were a maximum of 14 cases of myopathy among patients (n = 10107) taking statins (0.14%). Rhabdomyolysis was seen in altogether eight cases, five in the treatment group and three in the placebo group. A major drawback with the HPS study is that only 32% of all screened patients became randomized. In addition, the pre-run in phase where all patients were given 40 mg of simvastatin seems effectively to have sorted out cases with side-effects on statin treatment. The frequency of side-effects and especially myopathy presented has to be interpreted taking these facts into careful consideration. Taking into account the above facts, there are several reasons to believe that the HPS trial underestimates the risk for dose-dependent myopathia by statin treatment. We do not at this moment find it relevant to start treatment with 40 mg of simvastatin without titration from a lower dosage, and without measuring cholesterol in order to reach predefined goals. The Swedish national [3] or the European expert [4] panels are of the same opinion in contrast to WHO Medicines and Policy Department [5]. The problems with interaction with other concomitant medications as well as the mechanisms behind statin-induced muscle problems have to be further studied. Conflict of interest statement No conflict of interest was declared. M. Eriksson, B. Angelin, S. SjöbergFrom the Department of Medicine, Centre for Metabolism and Endocrinology, Karolinska University Hospital, Huddinge, Sweden References 1 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7– 22.CrossrefPubMedWeb of Science®Google Scholar 2 OTC statin: a bad decision for public health. Lancet 2004; 363: 1659.PubMedWeb of Science®Google Scholar 3 Swedish Medical Products Agency. Treatment recommendations. Läkemedelsverket 2003; 14: 9– 69. Google Scholar 4 De Backer G, Ambrosioni E, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2003; 24: 1601– 1610.PubMedWeb of Science®Google Scholar 5 World Health Organization. Priority Medicines for Europe and the World. Geneva: WHO, 2004Web of Science®Google Scholar Citing Literature Volume257, Issue3March 2005Pages 313-314 ReferencesRelatedInformation

Angioedema induced by tramadol?a potentially life-threatening condition

Tramadol is increasingly used for treatment of moderate-to-severe pain [7]. It differs from other opioids by combining weak opioid and monoaminergic modes of action. It is often considered effective and safe with a low potential for interactions, serious adverse drug reactions (ADR), and abuse, thus representing a drug of first choice in moderate-to-severe pain states both for short-term and long-term use [16, 24]. During the last few years, however, concerns have been raised about the side-effect profile of tramadol. For instance, hallucinations [8, 15, 18], serotonergic syndrome when combined with SSRIs [12, 17, 19], increased effect of oral anticoagulants with bleeding complications [1, 11, 22], risk of dependence and abuse even in patients with no history of drug abuse, and withdrawal symptoms even after recommended doses, have been reported [2, 5, 20, 23]. In Sweden, sales have increased during recent years. This has been accompanied by increased ADR reporting. For instance, 11 cases of angioedema possibly related to medication with tramadol have been reported to the Swedish Medical Products Agency. Angioedema is an uncommon but potentially life-threatening condition associated with some drugs [13], involving a vascular reaction characterized by non-pitting oedema of the dermis and subcutaneous fat or of the mucous membrane of the gastro-intestinal tract. Involvement of the oral cavity/pharynx and/or the upper respiratory tract can lead to acute respiratory distress due to airway obstruction, resulting in death unless emergency treatment is given [6, 9, 13]. Typical angioedema differs from urticaria because it usually lasts longer (2–4 days instead of hours) and is non-pruritic, non-painful, and nonerythematous [3]. However, angioedema and urticaria frequently co-exist. Because tramadol-induced angioedema has not been well-described, we present the six most serious cases of angioedema reported to us, involving the oral cavity/ pharynx and/or the upper respiratory tract. Four patients needed emergency treatment, and two of these at the ICU. Concomitant, on-going medication is given in Table 1.

Risk Factors for Extrapyramidal Symptoms During Treatment With Selective Serotonin Reuptake Inhibitors, Including Cytochrome P-450 Enzyme, and Serotonin and Dopamine Transporter and Receptor Polymorphisms

Extrapyramidal symptoms (EPS) are rare adverse drug reactions to selective serotonin reuptake inhibitors (SSRIs). This study aimed to investigate the potential risk factors for EPS associated with SSRIs including polymorphisms of cytochrome P-450 isoenzymes, and serotonin and dopamine transporters and receptors. All spontaneous adverse drug reaction reports received by the Swedish Medical Products Agency until December 1999 that were coded with EPS and judged to be at least possibly related to SSRI treatment were included in the study. Reporting physicians received a form for collection of relevant information including current and previous use of SSRIs and antipsychotics, alcohol or substance abuse, central nervous system damage, a history of epilepsy or EPS, and a family history of Parkinson disease. A blood sample was also requested for genotyping of selected cytochrome P-450, and serotonin and dopamine transporter and receptor mutations. A total of 64 cases of EPS were reported. Twenty-eight forms (46%) were returned, and 20 blood samples were obtained. Identified potential risk factors included age of 65 years or older and the presence of the A1 allele of the D2 dopamine receptor gene (DRD2) Taq1A polymorphism (relative risk, 2.4; 95% confidence interval, 1.2-4.5 vs literature controls). No relationship was apparent for sex, drug dose, or other genetic polymorphisms. At least 1 additional potential risk factor for EPS, such as a history of central nervous system damage, alcohol or substance abuse, epilepsy, Parkinson disease, previous or current exposure to antipsychotic drugs, concomitant treatment with other antidopaminergic or serotonergic agents, or a history of EPS, was found in 93% of the cases. The risk of EPS with SSRIs seems to increase with advanced age and with the presence of the A1 allele of DRD2 Taq1A polymorphism. Because of the small sample size of our study and the use of historical controls rather than patients who did not experience EPS during SSRIs treatment, the DRD2 finding is preliminary and needs to be replicated in other studies before firm conclusions can be drawn. At least 1 additional potential risk factor was found in almost all cases.

Approval times and the safety of new pharmaceuticals.

This study examined the relationship between the approval times for new pharmaceuticals and the number of adverse drug reactions reported to the Swedish Medical Products Agency. Yearly time-series data concerning the number of adverse drug reactions, as well as data concerning prices and quantities sold for 25 pharmaceutical substances during the period 1972-1996 were used. The results show that shorter approval times are associated with more adverse drug reactions, but also that the effects are quite small.

News from the Swedish Medical Products Agency

News from the Swedish Medical Products Agency

From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug.

NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4-hydroxyphenylpyruvate and 4-hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4-hydroxyphenylpyruvate dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4-hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.

Adverse effects of cosmetics and toiletries reported to the Swedish Medical Products Agency 1989-1994.

In Sweden, a cosmetic control system was introduced in 1989 at the Medical Products Agency (MPA). It consists of a register of importers, manufacturers and their products, and a voluntary adverse reaction reporting system identical to that concerning drugs. Between 1989 and 1994, MPA evaluated 191 reports concerning adverse effects of 253 cosmetics and toiletries. 90% of the reports concerned women and the top-ranking product category was moisturizers, followed by hair care products and nail products. The majority of the adverse effects reported involved only the skin, and 90% were eczematous reactions. 70% of the eczemas were classified as contact allergic, as patch tests were positive to the product as is, and in 1/2 of these products, 1 or more relevant allergens could be identified when tests were made with individual cosmetic ingredients. The most common offending ingredients were fragrances, toluenesulfonamide-formaldehyde resin and preservatives. The number of reports is small in relation to the expected number of cosmetic adverse effects, which can be explained by under-reporting. Efforts are being made to persuade Swedish physicians to report more often.