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Pioglitazone (Actos) for type 2 diabetes mellitus
The TGA advise that long-term use of pioglitazone may increase the risk of bladder cancer.
See the August 2011 In Brief.
Pioglitazone improves glycaemic control but it is unclear whether it improves diabetes-relatedclinical complications and mortality. Prescribers should consider this — along with recentlyemerging safety information — when assessing the ratio of potential harms and benefitsfor each patient.
Consider pioglitazone after other oral antidiabetic agents have been tried.
It can be considered when: either metformin or a sulfonylurea is contraindicated or not tolerated.
combination therapy with metformin and a sulfonylurea fails to provide adequateglycaemic control.
Insulin should also be considered instead of pioglitazone in these scenarios.
Pioglitazone is currently approved as combination therapy in patients with type 2 diabetesthat is inadequately controlled with insulin.
Pioglitazone is associated with weight gain, oedema and fluid retention and should not beused in patients with moderate to severe heart failure.
An analysis of data in a clinical trial database has found an increased rate of fractures of thearm, hand and lower leg among women using pioglitazone.
Doses should not be increased until after 8 weeks of treatment, as the full effect of the drugmay not be seen before this time. In clinical trials of glitazone treatment, 25% to 30% ofpatients had no improvement in glycaemic control.
PBS listing
• as triple oral therapy with maximally tolerated doses of metformin and a sulfonylurea.
Authority required (streamlined)
Pioglitazone is not listed on the Pharmaceutical Benefits
Pioglitazone can be used in patients with type 2 diabetes whose blood glucose concentrations are inadequatelycontrolled (HbA1c > 7%) either: Reason for PBS listing
• as dual oral therapy with metformin or a sulfonylurea Pioglitazone was recommended for listing by when combination therapy with metformin and a the Pharmaceutical Benefits Advisory Committee sulfonylurea is contraindicated or not tolerated; or (PBAC) on a cost-minimisation basis compared with • as dual therapy with insulin in patients with rosiglitazone.1 The indication was extended to include type 2 diabetes when HbA1c is > 7% despite triple oral therapy on a cost-minimisation basis compared concomitant use of insulin plus metformin or a sulfonylurea, or insulin alone where metforminis contraindicated.
Place in therapy
Pioglitazone’s effect on morbidity
and mortality is unclear

Pioglitazone is a thiazolidinedione (‘glitazone’)antidiabetic drug that should be considered Most clinical trials of pioglitazone have measured a third-line choice. Metformin (or, when this is surrogate outcomes such as effects on lipids or insulin contraindicated, a sulfonylurea) is usually the drug sensitivity over a period of 26 weeks or less. They did of first choice for type 2 diabetes. When combination not attempt to investigate whether pioglitazone alters therapy is required, metformin and a sulfonylurea the natural progression of diabetes.
is the combination of first choice. Pioglitazone can Only one study (the PROspective pioglitAzone Clinical Trial In macroVascular Events [PROactive] study) has • monotherapy (with metformin or a sulfonylurea) no investigated the effect of pioglitazone (in combination longer controls blood glucose but adding metformin with existing therapies) on diabetes-related morbidity or a sulfonylurea is contraindicated or not tolerated.3 and mortality.10 This study randomised 5238 patients withtype 2 diabetes and a history of cardiovascular disease • the combination of metformin and a sulfonylurea (except those with heart failure of New York Heart no longer adequately controls blood glucose levels.
Association [NYHA] Class II or above) to pioglitazone Insulin should also be considered instead of pioglitazone or placebo. It reported a significant improvement in a secondary endpoint of all-cause mortality, myocardial Pioglitazone (15–45 mg/day) decreased HbA infarction and stroke. However, as the primary endpoint* a further 0.6% to 1.7% when added to treatment did not reach significance, and the secondary endpoint with metformin, a sulfonylurea, or insulin compared was not defined in the original protocol, this could be with continuing monotherapy with these antidiabetic a chance finding and should be treated cautiously.
agents.4–7 Patients were enrolled in these trials because A recent meta-analysis pooled individual patient data they were inadequately controlled on initial monotherapy from 19 trials of pioglitazone and found a significant and often had HbA1c approaching 9% and beyond.
increase in the risk of serious heart failure and a Greater reductions in HbA1c are seen in patients who significant reduction in the composite endpoint of have poorer glycaemic control (HbA1c ≥ 9% before all-cause mortality, myocardial infarction and stroke.11 treatment) than patients with better control The meta-analysis is limited by the fact that many of the included trials were not designed to assess cardiovascular In an unpublished study of patients (n = 299) risk, and that 80% of the events included in the meta- inadequately controlled on metformin and a analysis came from the PROactive study. Furthermore, sulfonylurea, adding pioglitazone to metformin and there was no significant reduction in the composite the sulfonylurea (i.e. triple therapy) decreased HbA with an active comparator rather than placebo.
Dyslipidaemia is a problem in type 2 diabetesand contributes to the metabolic syndrome.
* The primary endpoint was all-cause mortality, non-fatal myocardial infarction Pioglitazone increases HDL–cholesterol concentration (including silent myocardial infarction), stroke, acute coronary syndrome, coronary and decreases triglyceride concentration.8 or leg revascularisation, or leg amputation.
Lifestyle changes remain important
Pioglitazone is approved for use with insulin
Dietary changes, regular exercise, weight loss Pioglitazone is approved as combination therapy and smoking cessation reduce cardiovascular risk in patients with type 2 diabetes who require insulin.† factors and improve glycaemic control for people Pioglitazone (15–30 mg/day) reduced HbA1c by a with diabetes. If glycaemic control has declined, further 1% to 1.3% over 16 weeks in patients assess the patient’s adherence to lifestyle changes inadequately controlled with insulin.7 Oedema and as part of your overall review and reinforce their hypoglycaemia occur more frequently when glitazones are combined with insulin (see Safety issues).
Metformin with a sulfonylurea is the
Consider initiating insulin rather
combination of first choice
than pioglitazone
In patients with type 2 diabetes, drug therapy often The addition of insulin or pioglitazone results in similar needs to increase over time to maintain glycaemic improvements in blood glucose levels when this is no control; 3 years after diagnosis, 50% of patients will longer adequately controlled by the combination of require more than one antidiabetic drug, increasing metformin and a sulfonylurea. In a single head-to-head trial of pioglitazone and bedtime NPH insulin among Metformin improves glycaemic control and reduces people who had failed dual therapy, pioglitazone reduced the incidence of macrovascular complications and death HbA1c levels by 1.9% ± 1.5% at 4 months while insulin among patients with type 2 diabetes.13 The sulfonylureas reduced HbA1c levels by 2.3% ± 1.5%.16 Follow-up in improve glycaemic control and reduce the incidence of this trial was only 4 months, so it is uncertain whether microvascular complications in diabetes.14 the response to treatment or the safety profile remains Metformin and a sulfonylurea is the preferred similar in both groups in the long term.
combination because of evidence that it reduces diabetic Consider using insulin instead of pioglitazone because: complications, because it is probably more cost-effective • insulin reduces the risk of diabetes complications14, and because clinicians have many years of experience whereas the effect of pioglitazone (alone or in combination with other oral antidiabetics) on What constitutes ‘intolerance’ of metformin
diabetes–related morbidity and mortality is still or sulfonylureas?
Metformin is contraindicated in people with severe • the long-term safety profile of insulin is better renal impairment or other risk factors for lactic acidosis.
defined. Many pioglitazone trials are of short duration It may also cause gastrointestinal adverse effects such (≤ 1 year). The only completed long-term trial of as diarrhoea, nausea and abdominal bloating, but these pioglitazone (in combination with existing therapies) are often transient and it is not usually necessary to stop in patients with type 2 diabetes (n = 5238; median treatment duration 2.8 years) reported significantlyhigher rates of heart failure, oedema and weight gain Hypoglycaemia is the most common adverse effect among the pioglitazone group than among those with sulfonylureas but can be minimised by splitting or reducing the daily dose. The elderly are at greaterrisk of hypoglycaemia, so shorter-acting agents such For information on initiating insulin see NPS News 56: as gliclazide or glipizide are preferred.
Managing hyperglycaemia in type 2 diabetes.
Both pioglitazone and the sulfonylureas are associated Other third-line choices include acarbose, repaglinide with weight gain so patients should not be switched (not currently PBS listed), or rosiglitazone.
to pioglitazone because of this adverse effect.
† The alternative glitazone, rosiglitazone should not be initiated in patients already using insulin because of increased risk of an ischaemic or congestive heart failure event.
Consult the Australian Medicines Handbook or refer to this review atwww.npsradar.org.au for additional information about contraindicationsand intolerance to metformin.
Safety issues
glitazones may be used cautiously but should be initiatedat the lowest dose.18 Particular care is advised in patients Pioglitazone should not be used in patients with who may be predisposed to developing heart failure, moderate to severe heart failure limiting physical such as the elderly or those receiving insulin.20 Pioglitazone more than doubles the risk of oedema, Hypoglycaemia is uncommon with pioglitazone alone compared with placebo or active comparator.17 but may occur when it is combined with a sulfonylurea In the PROactive study significantly more patients or insulin. Adjust the dose of sulfonylurea or insulin to using pioglitazone developed heart failure, compared reduce the risk of hypoglycaemia (see Dosing issues).
with those receiving placebo (11% vs 8%, p < 0.0001).10 Report suspected adverse reactions to the Adverse A consensus statement from the American Heart Drug Reactions Advisory Committee (ADRAC) online Association and the American Diabetes Association18 (www.tgasime.health.gov.au) or by using the 'Blue Card' notes that oedema is more common when glitazones are distributed with Australian Prescriber. For information used in combination therapy (around 7% of patients in about adverse drug reaction reporting, see the pioglitazone trials) and most likely when glitazones are used with insulin (12% to 18% when pioglitazone is The Therapeutic Goods Administration is monitoring Assess risk factors for heart failure before prescribing the safety information related to the glitazones and is glitazones — both medical (e.g. history of heart failure, currently liaising with sponsors to effect changes in the myocardial infarction or coronary heart disease; hyper- product information following recommendations by its tension; left ventricular hypertrophy; age > 70 years; expert advisory committees — the Australian Drug diabetes for > 10 years) and pharmacological Evaluation Committee (ADEC) and ADRAC.
(e.g. use of NSAIDs or calcium-channel blockers).
Fluid retention, peripheral oedema and the
Prescribers and patients should be alert for symptoms risk of heart failure
of developing heart failure. Checking weight dailycan provide an early warning of fluid accumulation.
Diabetes is a risk factor for heart disease and congestiveheart failure.18 Glitazones are associated with fluid Weight gain is a problem
retention and oedema, which could exacerbate existingheart failure or cause it to develop in patients at risk.
Weight gain is associated with all glitazones and is dose Regulatory agencies recently strengthened warnings dependent.8 Average weight gains of up to 4 kg were about heart failure among patients taking pioglitazone.19 seen in clinical trials.4–7,10 Weight gain is more likely whenpioglitazone is combined with sulfonylureas4 or insulin.7 Glitazones should not be used in patients with
moderate to severe heart failure. In patients who are
Weight continued to increase for as long as data were asymptomatic or have only mild cardiac insufficiency, recorded in trials (up to 84 weeks) so studies of longerduration are required to determine whether weight gaineventually plateaus in patients taking a glitazone.8 Refer to this review at www.npsradar.org.au to see the New York Heart Reinforce lifestyle measures for limiting weight gain Association grading of heart failure.
Pioglitazone appears to increase the risk
within 1 month.26 If a patient presents with symptoms of peripheral fractures among women
suggestive of liver disease, this should be seriouslyconsidered and investigated.
An analysis of patient data contained within themanufacturer's clinical trial database found a higher Drug interactions
risk of fracture among women taking pioglitazone Pioglitazone is metabolised by CYP2C8 and CYP3A4.
than in those taking a placebo or active comparator While no significant drug interactions have been (1.9 fractures vs 1.1 fractures per 100 patient–years).
reported to date, no formal pharmacokinetic interaction Most of these fractures were in the distal upper limb studies have been conducted.9 Caution is advised if (forearm, hand, wrist) or lower leg (foot, ankle, fibula combining pioglitazone with drugs metabolised by and tibia). No increase in risk of fracture was found these enzymes. Interactions reported between another antidiabetic drug, repaglinide, and gemfibrozil27 and One observational study suggested that the glitazones trimethoprim28 are mediated via CYP2C8 and could could cause bone loss among elderly women but not potentially occur if pioglitazone is used concurrently Glitazones may cause or
Agents affecting CYP3A4 include erythromycin, worsen macular oedema
ketoconazole, itraconazole, some ‘statins’(e.g. atorvastatin, simvastatin), calcium-channel A small number of postmarketing reports have blockers (e.g. diltiazem, verapamil), St John’s suggested that there may be an association between the glitazones and the development or worsening ofdiabetic macular oedema resulting in a decrease in There is an increased risk of hypoglycaemia when visual acuity.9,23 Any changes in vision reported by pioglitazone is combined with sulfonylureas or insulin.
patients taking pioglitazone should be investigated.
Because they induce fluid retention, combining Remain vigilant for signs of liver toxicity
pioglitazone with NSAIDs carries a theoreticalincreased risk of oedema and heart failure.24 The first available glitazone, troglitazone, was Consult the Australian Medicines Handbook or Actos withdrawn from the market after reports of liver product information for more detailed information toxicity. The risk of liver toxicity appears to be significantly lower with pioglitazone, but several casereports exist for both pioglitazone and rosiglitazone,including elevated liver enzymes concentrations, Dosing issues
hepatocellular damage, hepatitis and liver failure.8,24,25 The recommended dose of pioglitazone is 15–45 mg/day.
Patients with liver disease (including transaminase Patients should start at the lower dose of 15 mg/day, concentrations increased by more than 2.5 times particularly those at risk of hypoglycaemia.
the upper limit of normal) should not be started A proportion of patients does not respond to glitazone therapy with a decrease in fasting plasma glucose Glitazone-induced liver toxicity is unpredictable.
concentration and/or HbA1c (primary treatment failure).
Liver function tests are recommended before starting The non-responder rate observed in clinical trials of a glitazone and every 2 months thereafter. However, glitazones was 25% to 30%.8 One trial of pioglitazone monitoring liver function should not be viewed as 30 mg/day specifically divided patients into two groups always predicting the problem effectively: in some based on their responsiveness: in those patients who did cases of troglitazone liver toxicity, normal enzyme not respond (30 out of 70), the mean HbA1c decreased concentrations progressed to irreversible liver failure by only 0.1% after 3 months’ therapy.29 Allow time for response before
Information for patients
increasing dose
Pioglitazone doses should not be increased until • monitor for weight gain or ankle oedema 8 weeks after initiation of treatment; it has takenbetween 8 and 16 weeks for the full glycaemic • report any signs indicative of heart failure response to be seen in most of the glitazone trials (such as breathlessness during daily activities) at any given dose. As HbA1c testing is recommended • report signs of liver toxicity (abdominal pain, 3-monthly in patients whose therapy has changed or who are not meeting glycaemic goals, this seems an For more detailed information about pioglitazone, appropriate point to scrutinise the patient’s response suggest or provide the Actos consumer medicine and consider if any modifications to therapy are necessary. If patients continue to show no effect afterincreasing the dose, pioglitazone should be stopped.
1. Pharmaceutical Benefits Pricing Authority. Therapeutic 7. Rosenstock J, et al. Int J Clin Pract 2002;56:251–7.
20. Delea TE, et al. Diabetes Care 2003;26:2983–9.
relativity sheets. Canberra: Australian Government 8. Diamant M, Heine RJ. Drugs 2003;63:1373–405.
21. FDA Medwatch. Actos (pioglitazone) Tablets. Rockville, Department of Health and Ageing, 2007.
9. Eli Lilly Australia Pty Ltd. Actos product information Maryland: Food and Drug Administration, 2007.
http://www.health.gov.au/internet/wcms/publishing.nsf /Content/health-pbs-general-pricing-therelativity.htm 10. Dormandy JA, et al. Lancet 2005;366:1279–89.
/Actosmar0807.pdf (accessed 28 August 2007).
11. Lincoff AM, et al. JAMA 2007;298:1180–8.
22. Schwartz AV, et al. J Clin Endocrinol Metab 2. Pharmaceutical Benefits Advisory Committee. November 2007 PBAC outcomes — positive recommendations.
12. Turner RC, et al. JAMA 1999;281:2005–12.
23. European Medicines Agency. Press release: European Canberra: Australian Government Department of Health 13. UKPDS Group. Lancet 1998;352:854–65.
Medicines Agency: Committee for Medicinal Products and Ageing, 2007. http://www.healthconnect.gov.au 14. UKPDS Group. Lancet 1998;352:837–53.
for Human Use 11–14 December 2005.
/internet/main/publishing.nsf/Content/pbacrec-Nov07- 15. DeFronzo RA. Ann Intern Med 1999;131:281–303.
16. Aljabri K, et al. Am J Med 2004;116:230–5.
http://www.emea.europa.eu/pdfs/human/press 3. National Institute for Clinical Excellence. Guidance on 17. Richter B, et al. Cochrane Database Syst Rev /pr/42148405en.pdf (accessed 31 October 2007).
the use of glitazones for the treatment of type 2 24. Anonymous. Prescrire International 2002;11:170–6.
diabetes: Technology Appraisal 63. London: 18. Nesto RW, et al. Circulation 2003;108:2941–8.
National Institute for Clinical Excellence, 2003.
http://www.nice.org.uk/nicemedia/pdf/TA63_Glitazones 19. FDA Medwatch. Information for Healthcare _Review_Guidance.pdf (accessed 2 August 2007).
Professionals – Pioglitazone HCl (marketed as Actos, 26. Tolman KG, Chandramouli J. Clin Liver Dis Actoplus Met, and Duetact). Rockville, Maryland: Food 4. Kipnes MS, et al. Am J Med 2001;111:10–7.
and Drug Administration, 2007. http://www.fda.gov 27. Niemi M, et al. Diabetologia 2003;46:347–51.
5. Einhorn D, et al. Clin Ther 2000;22:1395–409.
/cder/drug/InfoSheets/HCP/pioglitazoneHCP.htm 28. Niemi M, et al. Br J Clin Pharmacol 2004;57:441–7.
6. Miyazaki Y, et al. Diabetes Care 2001;24:710–9.
29. Satoh N, et al. Diabetes Care 2003;26:2493–9.
Updated March 2008: addition of information on triple therapy.
Updated October 2007: fracture, macular oedema, information about PROactive.
The information contained in this material is derived from a critical analysis of a wide range of authoritative evidence.
Any treatment decisions based on this information should be made in the context of the clinical circumstances of each patient.

Source: http://www.nps.org.au/__data/assets/pdf_file/0003/35544/OKA8572_NPS_RADAR_Pioglitazone_V1.pdf

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