text: 01/12/2008 Kaletra 80mg/20mg Oral Solution 1. NAME OF THE MEDICINAL PRODUCT Kaletra (80 mg + 20 mg) / ml oral solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 5 ml of Kaletra oral solution contains 400 mg of lopinavir co- formulated with 100 mg of ritonavir as a pharmacokinetic enhancer. Name of the Quantity per ml - active substance Lopinavir 80 mg Ritonavir 20 mg - excipient (s) Alcohol (42% v/v) 356.3 mg High fructose corn syrup 168.6 mg Propylene glycol 152.7 mg Glycerol 59.6 mg Polyoxyl 40 hydrogenated castor oil 10.2 mg Acesulfame potassium 4.1 mg For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Oral solution The solution is light yellow to golden. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Kaletra is indicated for the treatment of HIV-1 infected adults and children above the age of 2 years, in combination with other antiretroviral agents. Most experience with Kaletra is derived from the use of the product in antiretroviral therapy naïve patients. Data in heavily pretreated protease inhibitor experienced patients are limited. There are limited data on salvage therapy on patients who have failed therapy with Kaletra. The choice of Kaletra to treat protease inhibitor experienced HIV-1 infected patients should be based on individual viral resistance testing and treatment history of patients (see sections 4.4 and 5.1). 4.2 Posology and method of administration Kaletra should be prescribed by physicians who are experienced in the treatment of HIV infection. Adult and adolescent use: the recommended dosage of Kaletra is 5 ml of oral solution (400/100 mg) twice daily taken with food. Paediatric use (2 years of age and above): the recommended dosage of Kaletra is 230/57.5 mg/m2 twice daily taken with food, up to a maximum dose of 400/100 mg twice daily. The 230/57.5 mg/m2 dosage might be insufficient in some children when co-administered with nevirapine or efavirenz. An increase of the dose of Kaletra to 300/75 mg/m2 should be considered in these patients. Dose should be administered using a calibrated oral dosing syringe. The oral solution is the recommended option for the most accurate dosing in children based on body surface area. However, if it is judged necessary to resort to soft capsules in children, they should be used with particular caution since they are associated with less precise dosing capabilities. Therefore, children receiving soft capsules might have higher exposure (with the risk of increased toxicity) or suboptinal exposure (with the risk of insufficient efficacy). Consequently when dosing children with soft capsules, therapeutic drug monitoring may be a useful tool to ensure appropriate lopinavir exposure in an individual patient. Paediatric Dosing Guidelines for the Dose 230/57.5 mg/m 2 Body Surface Twice Daily Oral Twice Daily Soft Area* (m2 ) Solution Dose (dose Capsule Dose in mg) (dose in mg) 0.25 0.7 ml (57.5/14.4 mg) NA 0.40 1.2 ml (96/24 mg) 1 soft capsule (133.3/33.3 mg) 0.50 1.4 ml (115/28.8 mg) 1 soft capsule (133.3/33.3 mg) 0.75 2.2 ml (172.5/43.1 1 soft capsule mg) (133.3/33.3 mg) 0.80 2.3 ml (184/46 mg) 2 soft capsules (266.6/66/6 mg) 1.00 2.9 ml (230/57.5 mg) 2 soft capsules (266.6/66/6 mg) 1.25 3.6 ml (287.5/71.9 2 soft capsules mg) (266.6/66/6 mg) 1.3 3.7 ml (299/74.8 mg) 2 soft capsules (266.6/66/6 mg) 1.4 4.0 ml (322/80.5 mg) 3 soft capsules (400/100 mg) 1.5 4.3 ml (345/86.3 mg) 3 soft capsules (400/100 mg) 1.7 5 ml (402.5/100.6 mg) 3 soft capsules (400/100 mg) * Body surface area can be calculated with the following equation BSA (m2) = √ (Height (cm) X Weight (kg) / 3600) Children less than 2 years of age: Kaletra is not recommended for use in children below 2 years of age due to insufficient data on safety and efficacy (see section 5.1). Paediatric patients should switch from Kaletra oral solution to soft capsules as soon as they are able to swallow the capsule formulation (see section 4.4). Hepatic impairment: In HIV-infected patients with mild to moderate hepatic impairment, an increase of approximately 30% in lopinavir exposure has been observed but is not expected to be of clinical relevance. (see section 5.2). No data are available in patients with severe hepatic impairment. Kaletra should not be given to these patients (see section 4.3). Renal impairment: No dose adjustment is necessary in patients with renal impairment. Caution is warranted when Kaletra is used in patients with severe renal impairment (see section 4.4). 4.3 Contraindications Patients with known hypersensitivity to lopinavir, ritonavir or any of the excipients. Patients with severe hepatic insufficiency. Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. These medicinal products include astemizole, terfenadine, oral midazolam (for caution on parenterally administered midazolam, see section 4.5), triazolam, cisapride, pimozide, amiodarone, ergot alkaloids (e.g. ergotamine, dihydroergotamine and ergonovine and methylergonovine) and vardenafil. Herbal preparations containing St John's wort (Hypericum perforatum) must not be used while taking lopinavir and ritonavir due to the risk of decreased plasma concentrations and reduced clinical effects of lopinavir and ritonavir (see section 4.5). Kaletra oral solution is contraindicated in children below the age of 2 years, pregnant women, patients with hepatic or renal failure and patients treated with disulfiram or metronidazole due to the potential risk of toxicity from the excipient propylene glycol (see section 4.4). 4.4 Special warnings and precautions for use Patients with coexisting conditions Hepatic impairment: the safety and efficacy of Kaletra has not been established in patients with significant underlying liver disorders. Kaletra is contraindicated in patients with severe liver impairment (see section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products. Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered. Renal impairment: since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Haemophilia: there have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship had been evoked, although the mechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding. Lipid elevations Treatment with Kaletra has resulted in increases, sometimes marked, in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing is to be performed prior to initiating Kaletra therapy and at periodic intervals during therapy. Particular caution should be paid to patients with high values at baseline and with history of lipid disorders. Lipid disorders are to be managed as clinically appropriate (see also section 4.5 for additional information on potential interactions with HMG-CoA reductase inhibitors). Pancreatitis Cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia. In most of these cases patients have had a prior history of pancreatitis and/or concurrent therapy with other medicinal products associated with pancreatitis. Marked triglyceride elevation is a risk factor for development of pancreatitis. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and Kaletra therapy should be suspended if a diagnosis of pancreatitis is made (see section 4.8). Hyperglycaemia New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been reported in patients receiving protease inhibitors. In some of these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycaemia. Fat redistribution & metabolic disorders Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8). Immune Reactivation Syndrome In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Osteonecrosis Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement. PR interval prolongation Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects. Rare reports of 2nd or 3rd degree atroventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving lopinavir/ritonavir. Kaletra should be used with caution in such patients (see section 5.1). Interactions with medicinal products Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra is likely to increase plasma concentrations of medicinal products that are primarily metabolised by CYP3A. These increases of plasma concentrations of co-administered medicinal products could increase or prolong their therapeutic effect and adverse events (see sections 4.3 and 4.5). The HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of Kaletra with simvastatin or lovastatin is not recommended due to an increased risk of myopathy including rhabdomyolysis. Caution must also be exercised and reduced doses should be considered if Kaletra is used concurrently with rosuvastatin or with atorvastatin, which is metabolised to a lesser extent by CYP3A4. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5). Particular caution must be used when prescribing Kaletra and medicinal products known to induce QT interval prolongation such as: chlorpheniramine, quinidine, erythromycin, clarithromycin. Indeed, Kaletra could increase concentrations of the co-administered medicinal products and this may result in an increase of their associated cardiac adverse events. Cardiac events have been reported with Kaletra in preclinical studies; therefore, the potential cardiac effects of Kaletra cannot be currently ruled out (see sections 4.8 and 5.3). Co administration of Kaletra with rifampicin is not recommended. Rifampicin in combination with Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when a higher dose of Kaletra is used but this is associated with a higher risk of liver and gastrointestinal toxicity. Therefore, this co administration should be avoided unless judged strictly necessary (see section 4.5). Other Patients taking the oral solution, particularly those with renal impairment or with decreased ability to metabolise propylene glycol (e.g. those of Asian origin), should be monitored for adverse reactions potentially related to propylene glycol toxicity (i.e. seizures, stupor, tachycardia, hyperosmolarity, lactic acidosis, renal toxicity, haemolysis) (see section 4.3). Kaletra is not a cure for HIV infection or AIDS. It does not reduce the risk of passing HIV to others through sexual contact or contamination with blood. Appropriate precautions should be taken. People taking Kaletra may still develop infections or other illnesses associated with HIV disease and AIDS. There are limited data on salvage therapy on patients who have failed with Kaletra. There are ongoing studies to further establish the usefulness of potential salvage therapy regimens (e.g. amprenavir or saquinavir). There are currently limited data on the use of Kaletra in protease inhibitor- experienced patients. Besides propylene glycol as described above, Kaletra oral solution contains alcohol (42% v/v) which is potentially harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or disease as well as for pregnant women and children. It may modify or increase the effects of other medicines. Kaletra oral solution contains up to 0.8 g of fructose per dose when taken according to the dosage recommendations. This may be unsuitable in hereditary fructose intolerance. Kaletra oral solution contains up to 0.3 g of glycerol per dose. Only at high inadvertent doses, it can cause headache and gastrointestinal upset. Furthermore, polyoxol 40 hydrogenated castor oil and potassium present in Kaletra oral solution may cause only at high inadvertent doses gastrointestinal upset. Patients on a low potassium diet should be cautioned. Concomitant use of Kaletra and fluticasone or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (see section 4.5). 4.5 Interaction with other medicinal products and other forms of interaction Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A in vitro. Co-administration of Kaletra and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse reactions. Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3). Kaletra has been shown in vivo to induce its own metabolism and to increase the biotransformation of some medicinal products metabolised by cytochrome P450 enzymes and by glucuronidation. This may result in lowered plasma concentrations and potential decrease of efficacy of co- administered medicinal products. Medicinal products that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in section 4.3. Antiretroviral agents Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs): Stavudine and Lamivudine: no change in the pharmacokinetics of lopinavir was observed when Kaletra was given alone or in combination with stavudine and lamivudine in clinical studies. Didanosine: it is recommended that didanosine be administered on an empty stomach; therefore, didanosine is to be given one hour before or two hours after Kaletra (given with food). The gastroresistant formulation of didanosine should be administered at least two hours after a meal. Zidovudine and Abacavir: Kaletra induces glucuronidation, therefore Kaletra has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. Tenofovir: when tenofovir disoproxil fumarate was co administered with Kaletra, tenofovir concentrations were increased by approximately 30% with no changes noted in lopinavir or ritonavir concentrations. Higher tenofovir concentrations could potentiate tenofovir associated adverse events, including renal disorders. Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Nevirapine: no change in the pharmacokinetics of lopinavir was apparent in healthy volunteers during nevirapine and Kaletra co-administration. Results from a study in HIV-positive paediatric patients revealed a decrease in lopinavir concentrations during nevirapine co-administration. The effect of nevirapine in HIV-positive adults is expected to be similar to that in paediatric patients and lopinavir concentrations may be decreased. The clinical significance of the pharmacokinetic interaction is unknown. No formal recommendation could be drawn on dosage adjustment when Kaletra is used in combination with nevirapine. However, based on clinical experience, Kaletra dose increase to 533/133 mg twice daily (~6.5 ml) may be considered when co-administered with nevirapine, particularly for patients in whom reduced lopinavir susceptibility is likely. Efavirenz: when used in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in multiple protease inhibitor-experienced patients, increasing the dose of Kaletra 33.3% from 400/100 mg (3 capsules) twice daily to 533/133 mg (4 capsules) twice daily yielded similar lopinavir plasma concentrations as compared to historical data of Kaletra 400/100 mg (3 capsules) twice daily. Dosage increase of Kaletra from 400/100 mg (5 ml) twice daily to 533/133 mg (~6.5 ml) twice daily should be considered when co-administered with efavirenz. Caution is warranted since this dosage adjustment might be insufficient in some patients. Co-administration with other HIV protease inhibitors (PIs): Kaletra (400/100 mg twice daily) has been studied in combination with reduced doses of amprenavir, indinavir, nelfinavir and saquinavir in steady- state controlled healthy volunteer studies relative to clinical doses of each HIV protease inhibitor in the absence of ritonavir. Comparisons to published pharmacokinetic data with ritonavir-enhanced amprenavir and saquinavir regimens are also described. Additionally, the effect of additional ritonavir on the pharmacokinetics of lopinavir are discussed. Note that the historical comparisons to ritonavir-enhanced protease inhibitor regimens should be interpreted with caution (see details of combinations below). Appropriate doses of HIV-protease inhibitors in combination with Kaletra with respect to safety and efficacy have not been established. Therefore, the concomitant administration of Kaletra with PIs requires close monitoring. Amprenavir: the concomitant use of Kaletra with amprenavir 750 mg twice daily, resulted in an increase in amprenavir AUC by 70% and of Cmin by 4.6- fold, relative to amprenavir 1200 mg twice daily alone. On the other hand, the AUC of lopinavir decreases by 38%. A dose increase of Kaletra may be necessary but may further affect concentrations of amprenavir. Combined with Kaletra, amprenavir concentrations were lower (approximately 30%) relative to boosted amprenavir (amprenavir 600 mg/ritonavir 100 mg) twice daily alone. Fosamprenavir: co-administration of standard doses of lopinavir/ritonavir with fosamprenavir results in a significant reduction in amprenavir concentrations. Co-administration of increased doses of fosamprenavir 1400 mg twice daily with lopinavir/ritonavir 533/133 mg twice daily to protease inhibitor experienced patients resulted in a higher incidence of gastrointestinal adverse events and elevations in triglycerides with the combination regimen without increases in virological efficacy, when compared with standard doses of fosamprenavir/ritonavir. Therefore, concomitant administration of these medicinal products is not recommended. Indinavir: indinavir 600 mg twice daily in combination with Kaletra produces similar indinavir AUC, higher Cmin (by 3.5-fold) and lower Cmax relative to indinavir 800 mg three times daily alone. Furthermore, concentrations of lopinavir do not appear to be affected when both medicinal products, Kaletra and indinivir, are combined, based on historical comparison with Kaletra alone. Nelfinavir: administration of nelfinavir 1000 mg twice daily in combination with Kaletra produces a similar nelfinavir Cmax and AUC and higher Cmin relative to nelfinavir 1250 mg twice daily alone. Additionally, concentrations of the active M8 metabolite of nelfinavir were increased. On the other hand, lopinavir AUC was decreased by 27% during nelfinavir co-administration with Kaletra. A dose increase of Kaletra may be necessary but may further affect concentrations of nelfinavir and its active metabolite. Higher doses of Kaletra have not been studied. Saquinavir: saquinavir 800 mg twice daily co-administered with Kaletra produces an increase of saquinavir AUC by 9.6-fold relative to saquinavir 1200 mg three times daily given alone. Saquinavir 800 mg twice daily co-administered with Kaletra resulted in an increase of saquinavir AUC by approximately 30% relative to saquinavir/ritonavir 1000/100 mg twice daily, and produces similar exposure to those reported after saquinavir/ritonavir 400/400 mg twice daily. When saquinavir 1200 mg twice daily was combined with Kaletra, no further increase of concentrations was noted. Furthermore, concentrations of lopinavir do not appear to be affected when both medicinal products, Kaletra and saquinavir, are combined, based on historical comparison with Kaletra alone. Ritonavir: Kaletra co-administered with an additional 100 mg ritonavir twice daily resulted in an increase of lopinavir AUC and Cmin of 33% and 64%, respectively, as compared to Kaletra alone. Other medicinal products: Acid reducing agents (omeprazole, ranitidine): in a study performed in healthy volunteers, no clinically relevant interaction has been observed when Kaletra tablets 400/100 mg twice daily was co administered with omeprazole or with ranitidine. Kaletra can be co administered with acid reducing agents with no dose adjustment. Antiarrhythmics: (bepridil, systemic lidocaine and quinidine): concentrations may be increased when co-administered with Kaletra. Caution is warranted and therapeutic concentration monitoring is recommended when available. Anticancer agents (eg vincristine, vinblastine): these agents may have their serum concentrations increased when co administered with lopinavir/ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents. Anticoagulants: warfarin concentrations may be affected when co- administered with Kaletra. It is recommended that INR (international normalised ratio) be monitored. Anticonvulsants (phenobarbital, phenytoin, carbamazepine): will induce CYP3A4 and may decrease lopinavir concentrations. In addition, co administration of phenytoin and lopinavir/ritonavir resulted in moderate decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co administering with lopinavir/ritonavir. Bupropion: in healthy volunteers, the AUC and Cmax of bupropion and of its active metabolite, hydroxybupropion, were decreased by about 50% when co-administered with lopinavir/ritonavir capsules 400/100 mg twice daily at steady-state. This effect may be due to induction of bupropion metabolism. Therefore, if the co administration of lopinavir/ritonavir with bupropion is judged unavoidable, this should be done under close clinical monitoring for bupropion efficacy, without exceeding the recommended dosage, despite the observed induction. Trazodone: in a pharmacokinetic study performed in healthy volunteers, concomitant use of low dose ritonavir (200 mg twice daily) with a single dose of trazodone led to an increase in plasma concentrations of trazodone (AUC increased by 2.4 fold). Adverse events of nausea, dizziness, hypotension and syncope were observed following co-administration of trazodone and ritonavir in this study. However, it is unknown whether the combination of lopinavir/ritonavir causes a similar increase in trazodone exposure. The combination should be used with caution and a lower dose of trazodone should be considered. Digoxin: plasma concentrations of digoxin may be increased when co administered with Kaletra. Caution is warranted and therapeutic drug monitoring of digoxin concentrations, if available, is recommended in case of co administration of Kaletra and digoxin. Particular caution should be used when prescribing Kaletra in patients taking digoxin as the acute inhibitory effect of ritonavir on Pgp is expected to significantly increase digoxin levels. The increased digoxin level may lessen over time as Pgp induction develops. Initiation of digoxin in patients already taking Kaletra is expected to result in lower increase of digoxin concentrations. Dihydropyridine calcium channel blockers: (e.g. felodipine, nifedipine, nicardipine): may have their serum concentrations increased by Kaletra. Disulfiram, metronidazole: Kaletra oral solution contains alcohol which can produce disulfiram-like reactions when co-administered with disulfiram or other medicinal products that produce this reaction. Lipid lowering agents: HMG-CoA reductase inhibitors which are highly dependent on CYP3A4 metabolism, such as lovastatin and simvastatin, are expected to have markedly increased plasma concentrations when co- administered with Kaletra. Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these medicinal products with Kaletra is not recommended. Atorvastatin is less dependent on CYP3A for metabolism. When atorvastatin was given concurrently with Kaletra, a mean 4.7-fold and 5.9-fold increase in atorvastatin Cmax and AUC, respectively, was observed. When used with Kaletra, the lowest possible dose of atorvastatin should be administered. Rosuvastatin is not dependent on CYP3A. However, when given concurrently with Kaletra a mean 5 fold and 2 fold increase in rosuvastatin Cmax and AUC, respectively, was observed. Caution should be exercised when Kaletra is co administered with rosuvastatin. Results from an interaction study with Kaletra and pravastatin reveal no clinically significant interaction. The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and interactions are not expected with Kaletra. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended. Dexamethasone: may induce CYP3A4 and may decrease lopinavir concentrations. Phosphodiesterase inhibitors: phosphodiesterase inhibitors which are dependent on CYP3A4 metabolism, such as tadalafil and sildenafil, are expected to result in an approximately 2 fold and 11 fold increase in AUC respectively, when co-administered with ritonavir containing regimens including Kaletra and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, synope, visual changes and prolonged erection. Particular caution must be used when prescribing sildenafil or tadalafil in patients receiving Kaletra with increased monitoring for adverse events. Co-administration of vardenafil with rtionavir containing regimens including Kaletra is expected to result in 49 fold increase in vardenafil AUC. The use of vardenafil with Kaletra is contraindicated (see section 4.3). Cyclosporin, sirolimus (rapamycin) and tacrolimus: concentrations may be increased when co administered with Kaletra. More frequent therapeutic concentration monitoring is recommended until plasma levels of these products have been stabilised. Ketoconazole and itraconazole: may have serum concentrations increased by Kaletra. High doses of ketoconazole and itraconazole (> 200 mg/day) are not recommended. Voriconazole: due to the potential for reduced voriconazole concentrations, co administration of voriconazole and low dose ritonavir (100 mg twice daily) as contained in Kaletra should be avoided unless an assessment of the benefit/risk to patient justifies the use of voriconazole. Clarithromycin: moderate increases in clarithromycin AUC are expected when co-administered with Kaletra. For patients with renal or hepatic impairment dose reduction of clarithromycin should be considered (see section 4.4). Buprenorphine: buprenorphine (dosed at 16 mg daily) co administered with lopinavir/ritonavir (dosed at 400/100 mg twice daily) showed no clinically significant interaction. Kaletra can be co administered with buprenorphine with no dose adjustment. Methadone: Kaletra was demonstrated to lower plasma concentrations of methadone. Monitoring plasma concentrations of methadone is recommended. Contraceptives:levels of ethinyl oestradiol were decreased when oestrogen- based oral contraceptives were co-administered with Kaletra. In case of co administration of Kaletra with contraceptives containing ethinyl oestradiol (whatever the contraceptive formulation e.g. oral or patch), alternative methods of contraception are to be used. Rifabutin: when rifabutin and Kaletra were co-administered for 10 days, rifabutin (parent substance and active 25-O-desacetyl metabolite) Cmax and AUC were increased by 3.5- and 5.7-fold, respectively. On the basis of these data, a rifabutin dose reduction of 75% (i.e. 150 mg every other day or 3 times per week) is recommended when administered with Kaletra. Further reduction may be necessary. Rifampicin: co administration of Kaletra with rifampicin is not recommended. Rifampicin administered with Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect. A dose adjustment of Kaletra 400 mg/400 mg twice daily has allowed compensating for the CYP 3A4 inducer effect of rifampicin. However, such a dose adjustment might be associated with ALT/AST elevations and with increase in gastrointestinal disorders. Therefore, this co administration should be avoided unless judged strictly necessary. If this co administration is judged unavoidable, increased dose of Kaletra at 400 mg/400 mg twice daily may be administered with rifampicin under close safety and therapeutic drug monitoring. The Kaletra dose should be titrated upward only after rifampicin has been initiated (see section 4.4). St John's wort: serum levels of lopinavir and ritonavir can be reduced by concomitant use of the herbal preparation St John's wort (Hypericum perforatum). This is due to the induction of drug metabolising enzymes by St John's wort. Herbal preparations containing St John's wort should therefore not be combined with lopinavir and ritonavir. If a patient is already taking St John's wort, stop St John's wort and if possible check viral levels. Lopinavir and ritonavir levels may increase on stopping St John's wort. The dose of Kaletra may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's wort (see section 4.3). Midazolam: midazolam is extensively metabolised by CYP3A4. Co administration with Kaletra may cause a large increase in the concentration of this benzodiazepine. A phenotyping cocktail study in 14 healthy volunteers showed an increase of AUC by about 13 fold with oral midazolam and an increase by about 4 fold with parenteral midazolam. Therefore, Kaletra should not be co administered with orally administered midazolam (see section 4.3), whereas caution should be used with co administration of Kaletra and parenteral midazolam. If Kaletra is co administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam should be considered especially if more than a single dose of midazolam is administered. Fluticasone propionate (interaction with ritonavir): in a clinical study where ritonavir 100 mg capsules twice daily were co − administered with 50 μg intranasal fluticasone propionate (4 times daily) for seven days in healthy subjects, the fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82 − 89%). Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway eg budesonide. Consequently, concomitant administration of Kaletra and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4). A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (eg beclomethasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period. The effects of high fluticasone systemic exposure on ritonavir plasma levels is yet unknown. Based on known metabolic profiles, clinically significant interactions are not expected between Kaletra and fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole. 4.6 Pregnancy and lactation There are no data from the use of Kaletra in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Kaletra should not be used during pregnancy unless clearly necessary. Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal product is excreted in human milk. HIV- infected women must not breast-feed their infants under any circumstances to avoid transmission of HIV. 4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. Patients should be informed that nausea has been reported during treatment with Kaletra (see section 4.8). Kaletra oral solution contains approximately 42% v/v alcohol. 4.8 Undesirable effects The safety of Kaletra has been investigated in 612 patients in Phase II/III clinical trials, of which 442 have received a dose of 400/100 mg (3 capsules) twice daily. In some studies, Kaletra was used in combination with efavirenz or nevirapine. The most common adverse event associated with Kaletra therapy was diarrhoea and was generally of mild to moderate severity. Discontinuation due to adverse reactions was 4.5% (naïve patients) and 9% (experienced patients) over a 48 week period. It is important to note that cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia. Furthermore, rare increases in PR interval have been reported during Kaletra therapy (see section 4.4: sections pancreatitis and lipid elevations). Increased CPK, myalgia, myositis, and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors. Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump). Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4). In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4). Adult patients Adverse reactions: The following adverse reactions of moderate to severe intensity with possible or probable relationship to Kaletra have been reported. The adverse reactions are displayed by system organ class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common >1/10, common > 1/100, < 1/10, uncommon > 1/1000, < 1/100. Undesirable effects in clinical studies in adult patients Infections and Uncommon Otitis media, bronchitis, infestations sinusitis, furunculosis, bacterial infections, viral infection Neoplasms benign, Uncommon Skin benign neoplasm, cyst malignant and unspecified (including cysts and polyps) Blood and lymphatic Uncommon Anaemia, leucopenia and system disorders lymphadenopathy Endocrine disorders Uncommon Hypergonadism male, Cushing syndrome, hypothyroidism Metabolic and Uncommon Avitminosis, dehydration, nutritional disorders oedema, increased appetite, lactic acidosis, obesity, anorexia, diabetes mellitus, hyperglycaemia, hypocholesteramia Psychiatric disorders Common Insomnia Uncommon Abnormal dreams, agitation, anxiety, confusion, depression, dyskinesia, emotional lability, decreased libido, nervousness, abnormal thinking Nervous system Common Headache, parathesia disorders Uncommon Dizziness, amnesia, ataxia, encephalopathy, facial paralysis, hypertonia, neuropathy, peripheral neuritis, somnolence, tremor, taste perversion, migraine, extrapyramidal syndrome Eye disorder Uncommon Abnormal vision, eye disorder Ear and labyrinth Uncommon Tinnitus disorders Cardiac disorders Uncommon Palpitation, lung oedema, myocardial infarc1 Vascular disorders Uncommon Hypertension, thrombophlebitis, vasculitis, varicose vein, deep thrombophlebitis, vascular disorder Respiratory, thoracic Uncommon Dyspnoea, rhinitis, cough and mediastinal increased disorders Gastrointestinal Very Diarrhoea disorders common Nausea, vomiting, abdominal Common pain, abnormal stools, dyspepsia, flatulence, gastrointestinal disorder Abdomen enlarged, constipation, dry mouth, Uncommon dysphagia, entercolitis, eructation, oesophagitis, faecal incontinence, gastritis, gastroenteritis, haemorrhagic colitis, mouth ulcerations, panreatitis2 , sialadenitis, stomatitis, ulcerative stomatitis, peridontitis Hepatobiliary Uncommon Cholecystitis, hepatitis, disorders hepatomegaly, liver fatty deposit, liver tenderness Skin and Common Rash, lipodystrophy, acne subcutaneous tissue disorders Uncommon Alopecia, dry skin, eczema, exfoliative dermatitis, maculopapular rash, nail disorder, Pruritis, seborrhoea, skin discoloration, skin ulcer, face oedema, sweating, skin striae Musculoskeletal and Uncommon Arthralgia, arthosis, myalgia, connective tissue back pain, joint disorder disorder Renal and urinary Uncommon Kidney calculus, urine disorders abnormality, albuminuria, hypercalcinuria, hypericaemia Reproductive system Uncommon Abnormal ejaculation, breast and breast disorders enlargement, gynecomastia, impotence, menorrhagia General disorders Common Asthemia, pain and administration site conditions Uncommon Chest pain, chest pain substernal, chills, fever, flu syndrome, malaise, peripheral oedema, drug interaction Investigations Very Increased triglycerides, common increased total cholesterol, (Grade 3or increased GGT 4) Increased glucose, increased amylase, increased SGOT/AST, Common increased SGPT/ALT, liver (Grade 3 or function tests abnormal 4) Decreased glucose tolerance, weight gain, weight loss, increased bilirubin, hormone level altered, lab test abnormal Uncommon 1 This event had a fatal outcome. 2 See section 4.4: pancreatitis and lipids Paediatric patients In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults. Undesirable effects in clinical studies in paediatric patients Infections and Common Viral infection infestations Nervous system Common Taste perversion disorders Gastrointestinal Common Constipation, vomiting, disorders pancreatitis* Hepatobiliary Common Hepatomegaly disorders Skin and Common Rash, dry skin subcutaneous tissue disorders General disorders and Common Fever administration site conditions Investigations Common Increased activated partial (Grade 3 or thromboplastin time, 4) decreased haemoglobin, decreased platelets, increased sodium, increased potassium, increased calcium, increased bilirubin, increased SGPT/ALT, increased SGOT/AST, increased total cholesterol, increased amylase, increased uric acid, decreased sodium, decreased potassium, decreased calcium, decreased neutrophils *see section 4.4: pancreatitis and lipids Post marketing experience Hepatitis, and rarely jaundice, have been reported in patients on Kaletra therapy in the presence or absence of identifiable risk factors for hepatitis. Stevens Johnson syndrome and erythema multiforme have been reported. Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4). 4.9 Overdose To date, there is limited human experience of acute overdose with Kaletra. The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/abnormal stool. The signs of toxicity observed in mice, rats or dogs included decreased activity, ataxia, emaciation, dehydration and tremors. There is no specific antidote for overdose with Kaletra. Treatment of overdose with Kaletra is to consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since Kaletra is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmaco-therapeutic group: protease inhibitor, ATC code: J05AE06 Mechanism of action : Lopinavir provides the antiviral activity of Kaletra. Lopinavir is an inhibitor of the HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in the production of immature, non-infectious virus. Effects on the electrocardiogram : QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) and 13.1(15.8) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily LPV/r, respectively. The induced QRS interval prolongation from 6 ms to 9.5 ms with high dose lopinavir/ritonavir (800/200 mg twice daily) contributes to QT prolongation. The two regimens resulted in exposures on Day 3 which were approximately 1.5 and 3-fold higher than those observed with recommended once daily or twice daily LPV/r doses at steady state. No subject experienced an increase in QTcF of 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec. Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ritonavir in the same study on Day 3. The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms in the 12 hour interval post dose.Maximum PR interval was 286 msec and no second or third degree heart block was observed (see section 4.4). Antiviral activity in vitro : the in vitro antiviral activity of lopinavir against laboratory and clinical HIV strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean IC50 of lopinavir against five different HIV-1 laboratory strains was 19 nM. In the absence and presence of 50% human serum, the mean IC50 of lopinavir against HIV-1IIIB in MT4 cells was 17 nM and 102 nM, respectively. In the absence of human serum, the mean IC50- of lopinavir was 6.5 nM against several HIV-1 clinical isolates. Resistance In vitro selection of resistance: HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro. HIV-1 has been passaged in vitro with lopinavir alone and with lopinavir plus ritonavir at concentration ratios representing the range of plasma concentration ratios observed during Kaletra therapy. Genotypic and phenotypic analysis of viruses selected in these passages suggest that the presence of ritonavir, at these concentration ratios, does not measurably influence the selection of lopinavir-resistant viruses. Overall, the in vitro characterisation of phenotypic cross-resistance between lopinavir and other protease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreased susceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility to amprenavir, saquinavir, and nelfinavir. Analysis of resistance in ARV-naïve patients: In a Phase II study (M97-720) through 204 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 11 of 16 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance. In a Phase III study (M98-863) of 653 patients randomised to receive stavudine plus lamivudine with either lopinavir/ritonavir or nelfinavir, 113 nelfinavir-treated subjects and 74 lopinavir/ritonavir-treated subjects had an HIV RNA above 400 copies/ml while on treatment from Week 24 through Week 96. Of these, isolates from 96 nelfinavir-treated subject and 51 lopinavir/ritonavir-treated subjects could be amplified for resistance testing. Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in protease, was observed in 41/96 (43%) subjects. Resistance to lopinavir, defined as the presence of any primary or active site mutations in protease (see above), was observed in 0/51 (0%) subjects. Lack of resistance to lopinavir was confirmed by phenotypic analysis. Analysis of resistance in PI-experienced patients: The selection of resistance to lopinavir in patients having failed prior protease inhibitor therapy was characterised by analysing the longitudinal isolates from 19 protease inhibitor-experienced subjects in 2 Phase II and one Phase III studies who either experienced incomplete virologic suppression or viral rebound subsequent to initial response to Kaletra and who demonstrated incremental in vitro resistance between baseline and rebound (defined as emergence of new mutations or 2-fold change in phenotypic susceptibility to lopinavir). Incremental resistance was most common in subjects whose baseline isolates had several protease inhibitor- associated mutations, but < 40-fold reduced susceptibility to lopinavir at baseline. Mutations V82A, I54V and M46I emerged most frequently. Mutations L33F, I50V and V32I combined with I47V/A were also observed. The 19 isolates demonstrated a 4.3-fold increase in IC50 compared to baseline isolates (from 6.2- to 43-fold, compared to wild-type virus). Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other protease inhibitors. The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients failing therapy with one or more protease inhibitors was assessed. Within this panel, the following mutations in HIV protease were associated with reduced in vitro susceptibility to lopinavir: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M. The median EC50 of lopinavir against isolates with 0 − 3, 4 − 5, 6 − 7 and 8 − 10 mutations at the above amino acid positions was 0.8, 2.7 13.5 and 44.0-fold higher than the EC50 against wild type HIV, respectively. The 16 viruses that displayed > 20-fold change in susceptibility all contained mutations at positions 10, 54, 63 plus 82 and/or 84. In addition, they contained a median of 3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90. In addition to the mutations described above, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir susceptibility from protease inhibitor experienced patients receiving Kaletra therapy. In addition to the mutations described above, mutations I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibility from protease inhibitor experienced patients receiving Kaletra therapy. Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change with additional data, and it is recommended to always consult current interpretation systems for analysing resistance test results. Antiviral activity of Kaletra in patients failing protease inhibitor therapy: the clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 patients previous failing therapy with multiple protease inhibitors. The EC50 of lopinavir against the 56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV. After 48 weeks of treatment with Kaletra, efavirenz and nucleoside reverse transcriptase inhibitors, plasma HIV RNA 400 copies/ml was observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with < 10 fold, 10 to 40-fold, and > 40 fold reduced susceptibility to lopinavir at baseline, respectively. In addition, virologic response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) patients with 0 − 5, 6 − 7, and 8 − 10 mutations of the above mutations in HIV protease associated with reduced in vitro susceptibility to lopinavir. Since these patients had not previously been exposed to either Kaletra or efavirenz, part of the response may be attributed to the antiviral activity of efavirenz, particularly in patients harbouring highly lopinavir resistant virus. The study did not contain a control arm of patients not receiving Kaletra. Cross resistance: Activity of other protease inhibitors against isolates that developed incremental resistance to lopinavir after Kaletra therapy in protease inhibitor experienced patients: The presence of cross resistance to other protease inhibitors was analysed in 18 rebound isolates that had demonstrated evolution of resistance to lopinavir during 3 Phase II and one Phase III studies of Kaletra in protease inhibitor-experienced patients. The median fold IC50 of lopinavir for these 18 isolates at baseline and rebound was 6.9- and 63-fold, respectively, compared to wild type virus. In general, rebound isolates either retained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir, saquinavir and atazanavir. Modest decreases in amprenavir activity were noted with a median increase of IC50 from 3.7- to 8-fold in the baseline and rebound isolates, respectively. Isolates retained susceptibility to tipranavir with a median increase of IC50 in baseline and rebound isolates of 1.9- and 1.8–fold, respectively, compared to wild type virus. Please refer to the Aptivus Summary of Product Characteristics for additional information on the use of tipranavir, including genotypic predictors of response, in treatment of lopinavir- resistant HIV-1 infection. Clinical pharmacodynamic data The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma HIV RNA levels and CD4 counts) have been investigated in a controlled study of Kaletra of 48 weeks duration, and in additional studies of Kaletra of 360 weeks duration. Adult Use Patients without prior antiretroviral therapy Study M98-863 is a randomised, double-blind trial of 653 antiretroviral treatment naïve patients investigating Kaletra (400/100 mg twice daily) compared to nelfinavir (750 mg three times daily) plus nucleoside reverse transcriptase inhibitors. By intent to treat analysis where patients with missing values are considered virologic failures, the proportion of patients at 48 weeks with HIV RNA < 400 copies/ml in the Kaletra arm was 75% and 63% in the nelfinavir arm. Mean baseline CD4 cell count was 259 cells/mm3 (range: 2 to 949 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to 6.8 log10 copies/ml). Through 48 weeks of therapy, the proportion of patients in the Kaletra arm with plasma RNA < 50 copies/ml was 67% and 52% in the nelfinavir arm. The mean increase from baseline in CD4 cell count was 207 cells/mm3 in the Kaletra arm and 195 cells/mm3 in the nelfinavir arm. Through 48 weeks of therapy, a statistically significantly higher proportion of patients in the Kaletra arm had HIV RNA < 50 copies/ml compared to the nelfinavir arm. Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reverse transcriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360 weeks of treatment. One hundred patients were originally treated with Kaletra in the study (including 51 patients receiving 400/100 mg twice daily and 49 patients at either 200/100 mg twice daily or 400/200 mg twice daily). All patients converted to open-label Kaletra at the 400/100 mg twice daily dose between week 48 and week 72. Sixty one patients completed the study (35 patients received the recommended 400/100 mg twice daily dose throughout the study). Through 360 weeks of treatment, the proportion of patients with HIV RNA < 400 (< 50) copies/ml was 61% (59%), and the corresponding mean increase in CD4 cell count was 501 cells/mm3. Thirty- nine patients (39%) discontinued the study, including 16 (16%) discontinuations due to adverse events, one of which was associated with a death. Patients with prior antiretroviral therapy Study M97-765 is a randomised, double-blind trial evaluating Kaletra at two dose levels (400/100 mg and 400/200 mg, both twice daily) plus nevirapine (200 mg twice daily) and two nucleoside reverse transcriptase inhibitors in 70 single protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor naïve patients. Median baseline CD4 cell count was 349 cells/mm3 (range 72 to 807 cells/mm3) and median baseline plasma HIV-1 RNA was 4.0 log10 copies/ml (range 2.9 to 5.8 log10 copies/ml). By intent-to-treat analysis where patients with missing values are considered virologic failures, the proportion of patients with HIV RNA < 400 (< 50) copies/ml at 24 weeks was 75% (58%) and the mean increase from baseline in CD4 cell count was 174 cells/mm3 for the 36 patients receiving the 400/100 mg dose of Kaletra. M98-957 is a randomised, open-label study evaluating Kaletra treatment at two dose levels (400/100 mg and 533/133 mg, both twice daily) plus efavirenz (600 mg once daily) and nucleoside reverse transcriptase inhibitors in 57 multiple protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor naïve patients. Between week 24 and 48, patients randomised to a dose of 400/100 mg were converted to a dose of 533/133 mg. Median baseline CD4 cell count was 220 cells/mm3 (range13 to 1030 cells/mm3). By intent-to-treat analysis of both dose groups combined (n=57), where patients with missing values are considered virologic failures, the proportion of patients with HIV RNA < 400 copies/ml at 48 weeks was 65% and the mean increase from baseline CD4 cell count was 94 cells/mm3. Paediatric Use M98-940 is an open-label study of a liquid formulation of Kaletra in 100 antiretroviral naïve (44%) and experienced (56%) paediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naïve. Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m2 or 300 mg lopinavir/75 mg ritonavir per m2. Naïve patients also received nucleoside reverse transcriptase inhibitors. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after 3 weeks of therapy in each patient. Subsequently, all patients were continued on the 300/75 mg per m2 dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14 patients less than 2 years old and 6 patients one year or less. Mean baseline CD4 cell count was 838 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/ml. Through 48 weeks of therapy, the proportion of patients with HIV RNA < 400 copies/ml was 84% for antiretroviral naïve patients and 75% for antiretroviral experienced patients and the mean increase from baseline in CD4 cell count were 404 cells/mm3 and 284 cells/mm3 respectively. 5.2 Pharmacokinetic properties The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolised by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of Kaletra 400/100 mg twice daily yields mean steady-state lopinavir plasma concentrations 15 to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The in vitro antiviral EC50 of lopinavir is approximately 10- fold lower than that of ritonavir. Therefore, the antiviral activity of Kaletra is due to lopinavir. Absorption: multiple dosing with 400/100 mg Kaletra twice daily for 3 to 4 weeks and without meal restriction produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 9.6 ± 4.4 μg/ml, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 5.5 ± 4.0 μg/ml. Lopinavir AUC over a 12 hour dosing interval averaged 82.8 ± 44.5 μg•h/ml. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Effects of food on oral absorption: Kaletra soft capsules and liquid have been shown to be bioequivalent under nonfasting conditions (moderate fat meal). Administration of a single 400/100 mg dose of Kaletra soft capsules with a moderate fat meal (500 – 682 kcal, 22.7 –25.1% from fat) was associated with a mean increase of 48% and 23% in lopinavir AUC and Cmax, respectively, relative to fasting. For Kaletra oral solution, the corresponding increases in lopinavir AUC and Cmax were 80% and 54%, respectively. Administration of Kaletra with a high fat meal (872 kcal, 55.8% from fat) increased lopinavir AUC and Cmax by 96% and 43%, respectively, for soft capsules, and 130% and 56%, respectively, for oral solution. To enhance bioavailability and minimise variability Kaletra is to be taken with food. Distribution: at steady state, lopinavir is approximately 98 − 99% bound to serum proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin, however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg Kaletra twice daily, and is similar between healthy volunteers and HIV-positive patients. Metabolism: in vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system, almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir and therefore, increases plasma levels of lopinavir. A 14C lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was due to parent active substance. At least 13 lopinavir oxidative metabolites have been identified in man. The 4-oxo and 4-hydroxymetabolite epimeric pair are the major metabolites with antiviral activity, but comprise only minute amounts of total plasma radioactivity. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism, and likely the induction of lopinavir metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks. Elimination: after a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and faeces, respectively. Unchanged lopinavir accounted for approximately 2.2% and 19.8% of the administered dose in urine and faeces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The effective (peak to trough) half-life of lopinavir over a 12 hour dosing interval averaged 5 − 6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 l/h. Special Populations Paediatrics: There are limited pharmacokinetic data in children below 2 years of age. The pharmacokinetics of Kaletra 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studied in a total of 53 paediatric patients, ranging in age from 6 months to 12 years. The lopinavir mean steady-state AUC, Cmax, and Cmin were 72.6 ± 31.1 μg•h/ml, 8.2 ± 2.9 μg/ml and 3.4 ± 2.1 μg/ml, respectively after Kaletra 230/57.5 mg/m2 twice daily without nevirapine (n=12), and were 85.8 ± 36.9 μg•h/ml, 10.0 ± 3.3 μg/ml and 3.6 ± 3.5 μg/ml, respectively after 300/75 mg/m2 twice daily with nevirapine (n=12). The 230/57.5 mg/m2 twice daily regimen without nevirapine and the 300/75 mg/m2 twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen without nevirapine. Kaletra soft capsules and Kaletra oral solution are bioequivalent under nonfasting conditions. Gender, Race and Age: Kaletra pharmacokinetics have not been studied in the elderly. No age or gender related pharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due to race have not been identified. Renal Insufficiency: Kaletra pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency. Hepatic Insufficiency: The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to moderate hepatic impairment were compared with those of HIV-infected patients with normal hepatic function in a multiple dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited increase in total lopinavir concentrations of approximately 30% has been observed which is not expected to be of clinical relevance (see section 4.2). 5.3 Preclinical safety data Repeat-dose toxicity studies in rodents and dogs identified major target organs as the liver, kidney, thyroid, spleen and circulating red blood cells. Hepatic changes indicated cellular swelling with focal degeneration. While exposure eliciting these changes were comparable to or below human clinical exposure, dosages in animals were over 6-fold the recommended clinical dose. Mild renal tubular degeneration was confined to mice exposed with at least twice the recommended human exposure; the kidney was unaffected in rats and dogs. Reduced serum thyroxine led to an increased release of TSH with resultant follicular cell hypertrophy in the thyroid glands of rats. These changes were reversible with withdrawal of the active substance and were absent in mice and dogs. Coombs-negative anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens with histiocytosis were seen in rats but not other species. Serum cholesterol was elevated in rodents but not dogs, while triglycerides were elevated only in mice. During in vitro studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% at the highest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 7-fold total and 15-fold free peak plasma levels achieved in humans at the maximum recommended therapeutic dose. In contrast, similar concentrations of lopinavir/ritonavir demonstrated no repolarisation delay in the canine cardiac Purkinje fibres. Lower concentrations of lopinavir/ritonavir did not produce significant potassium (HERG) current blockade. Tissue distribution studies conducted in the rat did not suggest significant cardiac retention of the active substance; 72-hour AUC in heart was approximately 50% of measured plasma AUC. Therefore, it is reasonable to expect that cardiac lopinavir levels would not be significantly higher than plasma levels. In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged PR interval and bradycardia. These effects have been assumed to be caused by electrolyte disturbance. The clinical relevance of these preclinical data is unknown, however, the potential cardiac effects of this product in humans cannot be ruled out (see also sections 4.4 and 4.8). In rats, embryofoetotoxicity (pregnancy loss, decreased foetal viability, decreased foetal body weights, increased frequency of skeletal variations) and postnatal developmental toxicity (decreased survival of pups) was observed at maternally toxic dosages. The systemic exposure to lopinavir/ritonavir at the maternal and developmental toxic dosages was lower than the intended therapeutic exposure in humans. Long-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a nongenotoxic, mitogenic induction of liver tumours, generally considered to have little relevance to human risk. Carcinogenicity studies in rats revealed no tumourigenic findings. Lopinavir/ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Oral solution contains: alcohol (42% v/v), high fructose corn syrup, propylene glycol, purified water, glycerol, povidone, magnasweet-110 flavour (mixture of monoammonium glycyrrhizinate and glycerol), vanilla flavour (containing p-hydroxybenzoic acid, p-hydroxybenzaldehyde, vanillic acid, vanillin, heliotrope, ethyl vanillin), polyoxyl 40 hydrogenated castor oil, cotton candy flavour (containing ethyl maltol, ethyl vanillin, acetoin, dihydrocoumarin, propylene glycol), acesulfame potassium, saccharin sodium, sodium chloride, peppermint oil, sodium citrate, citric acid, menthol. 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). In use storage: If kept outside of the refrigerator, do not store above 25°C and discard any unused contents after 42 days (6 weeks). It is advised to write the date of removal from the refrigerator on the package. Avoid exposure to excessive heat. 6.5 Nature and contents of container Amber coloured multiple-dose polyethylene terephthalate (PET) bottles in a 60 ml size. Each pack contains 5 bottles of 60 ml (300 ml). The pack also contains 5 x 5 ml syringes with 0.1 ml graduations from 0 to 5 ml (400/100 mg). 6.6 Special precautions for disposal and other handling No special requirements. 7. MARKETING AUTHORISATION HOLDER Abbott Laboratories Limited Queenborough Kent ME11 5EL United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) EU/1/01/172/003 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 20 March 2001 Date of last renewal: 20 March 2006 10. DATE OF REVISION OF THE TEXT 30 October 2008


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NHRA stars visit International Bowling Campus
September 25, 2010 by Texas Motorplex
Filed under Featured Articles, Latest News
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ARLINGTON, Texas (Sept. 24) – Five-time world champion drag racer Jeg Coughlin Jr. is best known for his exploits behind the wheel of his 210-mph JEGS.com Chevrolet Cobalt Pro Stock car. But when the affable pro from Delaware, Ohio, isn't zipping dow the strip, he can usually be found at the local bowling alley, knocking down pins.
So when he got a chance to visit the International Bowling Campus in Arlington, Texas, prior to the start of this weekend's race in nearby Ennis, Coughlin jumped at the opportunity. A United States Bowling Congress member and long-time league bowler, Coughlin was joined at the IBC by fellow Pro Stock driver, Allen Johnson, a youth bowler when he was a boy.
The trip included a guided tour of the International Bowling Museum and Hall of Fame, a look behind the scenes of the research side of the International Training and Research Center, and some time on the lanes with USBC Silver coach Bryan O'Keefe and Team USA member Mike Fagan on the training side of the ITRC.
"I think from a novice standpoint, learning about the different balls and lane conditions was great, and I have a lot to digest from this tour," said Coughlin, who averaged 183 in 63 games last year at Delaware Lanes in his hometown. "The museum and hall of fame were neat to see, and I really enjoyed the technology side of things. There are a lot of similarities between racing and bowling."
During an NHRA-leading seven-win season in 2009, Coughlin and nine of his fellow drivers and crew members, including Johnson, made time to compete in the 2009 USBC Open Championships in Las Vegas, which featured a near-record 17,200 teams.
As Coughlin continues to learn the nuances of bowling, his experience at the world's largest participatory sporting event and the IBC will stand out.
"Being here and being at the Open were real eye-openers for me," said Coughlin, who ranks ninth all-time with 66 career NHRA wins and fourth with 52 Pro Stock victories. "I've bowled locally at home, but the atmosphere and the conditions are a lot different. I know I have a lot to learn, but I'm looking forward to it."
Now, the 1998 NHRA Rookie of the Year has found a way to combine his passions for racing and bowling. He plans to install a pair of bowling lanes in his new shop at his home just north of Columbus, Ohio.
"I think it will be fun for family and friends to be able to enjoy the sport of bowling, too," Coughlin said. "And with the traveling I do, it is nice to be able to stay close to home when I'm in town but still spend time doing something I enjoy."
Saturday Racing Action Set to Begin Soon
September 25, 2010 by Texas Motorplex
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The track is being prepared and Sportsman racing will begin shortly. It is dry and 73 degrees outside and feels perfect for drag racing. The first pro session will begin with Top Fuel around 11:15am this morning. The final pro qualifying session will start around 2:30pm this afternoon. Get your tickets now and come on out to be a part of history.
First Day of Pro Qualifying in the Books
September 24, 2010 by Texas Motorplex
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The first day of pro qualifying got underway Friday afternoon with the Pro Stock Motorcycles. Karen Stoffer took the top spot with a 6.953, followed closely by Eddie Krawiec with a 6.955. Steve Johnson rounded out the Top 3 in the first round.
In pro stock cars Jason line lead the pack with a 6.644 followed by Mike Edwards and Line's teammate Greg Anderson in third.
The first round of Funny Cars saw Tim Wilkerson grab the number one spot with a 4.325. Jeff Arend drove his DHL Solara into second place with a time of 4.34. John Force closed out the top three and increased his lead over Robert Hight to five.
Top Fuel point's leader, Larry Dixon, added to his lead by grabbing the top spot with a time of 3.962. Brandon Bernstein and Cory McClenathan finished second and third.
Round two of Pro Stock Motorcycles saw Karen Stoffer keep her number one qualifying position while Eddie Krawiec set a new track speed record of 195.03mph.
In Pro Stock Car, Allen Johnson climbed his way to the top spot with a time of 6.632. First round leader Jason Line held on to the second place position followed by Mike Edwards.
Cruz Pedregon, who has won this event twice, powered his way to the top qualifier spot with a 4.129. Jeff Arend and Tim Wilkerson flip-flopped places to end the second round.
Top Fuel saw better times from everyone, but Larry Dixon was able to hold onto his number one qualifiers position with a 3.852. Cory McClenathan and Brandon Bernstein swapped places but remained in the top three at the end of the day.
Gates will open Saturday at 7:30am with the third round of Pro Stock Qualifying starting around 11:15am. Tickets are still available to catch all of the action at the 25th Anniversary O'Reilly Fall Nationals.
Racing is Underway at the 25th O'Reilly Fall Nationals
September 24, 2010 by Texas Motorplex
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The 25th Anniversary O'Reilly Fall Nationals at the Texas Motorplex in Ennis is underway. The first round of Pro Qualifying is finished with the second round scheduled for later tonight. The weather is great so come on out and catch all of the action tonight. You can also find updates for each round of qualifying under the Fall Nationals section of texasmotorplex.com.
September 23, 2010 by Texas Motorplex
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ENNIS, Texas (Sept. 23, 2010) – Texas Motorplex opened its gates for an NHRA national event for the first time in September 1986. It was a turning point in drag racing history, as no other facility had featured an all-concrete racing surface and fan and racer amenities as never seen before in racing.
The year was 1986. What else happened that year?
- "We Are The World" won a Grammy as Record of the Year
- "No Jacket Required" by Phil Collins won Grammy for Album of the Year.
- First ten musicians are voted into the Rock & Roll Hall of Fame.
- Top box office films include Top Gun, Crocodile Dundee, Platoon and Aliens.
- IBM unveils the PC Convertible – the first laptop computer.
- Roger Clemens set the record for the most strikeouts in a nine-inning MLB game, striking out 20 batters.
- The first Martin Luther King Day is observed.
- Space shuttle Challenger disintegrates 73 seconds after launch, killing the crew of astronauts.
- "Out of Africa" wins best picture of the year.
- The Chernobyl disaster happened.
- Geralda Rivera opens Al Capone's secrete vault on "The Mystery of Al Capone's Vault" TV show discovering only a bottle of moonshine.
- Hands Across America – at least 5,000,000 people form a human chain from NYC to Long Beach CA, to raise money to fight hunger and homelessness.
- The Statue of Liberty is reopened to the public after extensive refurbishing.
- Georgia O'Keefe, American Artist died.
- Smoking is banned on all public transport including planes, trains, busses, and coaches.
The Texas Motorplex was the first all-concrete stadium-style drag racing facility ever constructed. Built in 1986, The Texas Motorplex has been the place of many drag racing milestones and world record performances. The Billy Meyer-owned facility hosts a number of racing and car show events between March and November each year and also features the Champions Club – an 11,000 square-foot facility – that serves fully catered events throughout the year.


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Drachuk Family History & Genealogy
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According to one Drachuk family researcher, the Drachuk family is from western Ukrania and the surname "Drachuk" means, loosely, "fighter." This page is dedicated to the complete history of the Drachuk surname, Drachuk etymology, and stories of people with the Drachuk name. Drachuk family history has a complex evolution whose details have been accumulated over the years by Drachuk family researchers. The last name Drachuk is an old family line that has migrated all across the world over time, and as the Drachuk family has migrated, it has evolved making it's origin a challenge to unearth.
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- John Drachuk 1888 - 1967
- Amelia Drachuk 1906 - 2002
- Frances K Drachuk 1930 - 1999
- Alexander Drachuk 1923 - 1975
- Tony Drachuk 1920 - 1983
- Pauline G Drachuk 1915 - 2004
- Anita Lyndal Drachuk 1919 - 2007
- Sidor F Drachuk 1912 - 2003
- Daniel Drachuk 1924 - 2001
- Christina Drachuk 1922 - 2011
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- Amelia Drachuk lived 97 years
- Amelia Drachuk lived 96 years
- Pauline G Drachuk lived 89 years
- Alexander Drachuk lived 52 years
- Tony Drachuk lived 63 years
- Pauline G Drachuk lived 89 years
- Anita Lyndal Drachuk lived 88 years
- Sidor F Drachuk lived 91 years
- Daniel Drachuk lived 77 years
- Christina Drachuk lived 89 years
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Last names similar to Drachuk
Drachus, Draciary, Dracic, Dracico, Dracien, Dracikieicz, Dracikiewicz, Dracilowski, Dracine, Dracini, Dracinskaja, Dracius, Drack, Dracka, Drackart, Drackbar, Dracke, Drackeford, Drackemiller, DrackenFind Drachuk records
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4-Pk. of 15-LED Headlamps
Item # E4X6-592270
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4-Pk. of 15-LED Headlamps. Flashlights... who needs 'em?
Not you! You've got bright, hands-free light at your disposal in the form of these Headlamps. Switch between 3, 9 or 15-LED modes with the push of a button, and rotate the lens up to 90°. Comfortable, adjustable headband. Bright 33-lumen output. Each uses 3 AAA batteries (included).
Use your noodle... get this Close-Out bargain ONLINE today!
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4-Pk. 15-LED Headlamps is rated out of 5 by 2.Rated 5 out of 5 by PATRICK L from Not exactly what I expected but will suffice!Date published: 2014-05-06Rated 5 out of 5 by PATRICIA from I have always had excellent service from The Sportsman's Guide. The products was as stated.Date published: 2014-05-02
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Language school owner. Brazilian married to peruvian girl. Speak Spanish and love the Latin culture. organizer of Spanish, Portuguese, French, Italian, German, English meetups.
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text: The Goodyear Tire and Rubber Company said yesterday that Samir F. Gibara, its president and chief operating officer, would become chief executive, effective on Jan. 1. Mr. Gibara, 55, will take over from Stanley C. Gault, who is also chairman of the Akron-based tire company. Mr. Gault, 69, will remain chairman until June 30. The company's board said it intended to name Mr. Gibara chairman next June. Mr. Gibara was named president and chief operating officer April 10. Mr. Gibara, a Harvard M.B.A. born in Cairo and fluent in several languages, is a 30-year Goodyear veteran whose experience includes executive posts with Goodyear in Canada and Europe.


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Silk Touch Toddler Polo by Precious Cargo
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A pint-sized version of our grown-up shrink- and wrinkle- resistant style. |5-ounce, 65/35 poly/cotton pique Double-needle stitching throughout for durabilityFlat knit collar and cuffs2-button placket with dyed-to-match buttons


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Open AccessThis article is
MDPI and ACS Style
- freely available
- re-usable
Sensors 2011, 11(1), 674-695; doi:10.3390/s110100674
Hydrogen Sensors Using Nitride-Based Semiconductor Diodes: The Role of Metal/Semiconductor Interfaces
Received: 21 December 2010 / Accepted: 6 January 2011 / Published: 11 January 2011
(This article belongs to the Special Issue Gas Sensors - 2010)
Abstract: In this paper, I review my recent results in investigating hydrogen sensors using nitride-based semiconductor diodes, focusing on the interaction mechanism of hydrogen with the devices. Firstly, effects of interfacial modification in the devices on hydrogen detection sensitivity are discussed. Surface defects of GaN under Schottky electrodes do not play a critical role in hydrogen sensing characteristics. However, dielectric layers inserted in metal/semiconductor interfaces are found to cause dramatic changes in hydrogen sensing performance, implying that chemical selectivity to hydrogen could be realized. The capacitance-voltage (C-V) characteristics reveal that the work function change in the Schottky metal is not responsible mechanism for hydrogen sensitivity. The interface between the metal and the semiconductor plays a critical role in the interaction of hydrogen with semiconductor devises. Secondly, low-frequency C-V characterization is employed to investigate the interaction mechanism of hydrogen with diodes. As a result, it is suggested that the formation of a metal/semiconductor interfacial polarization could be attributed to hydrogen-related dipoles. In addition, using low-frequency C-V characterization leads to clear detection of 100 ppm hydrogen even at room temperature where it is hard to detect hydrogen by using conventional current-voltage (I-V) characterization, suggesting that low-frequency C-V method would be effective in detecting very low hydrogen concentrations.
GaN; AlGaN; Schottky barrier diodes; hydrogen sensors
This is an open access article distributed under the
Creative Commons Attribution License which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is properly cited.
Export to BibTeX | EndNote
MDPI and ACS Style
Irokawa, Y. Hydrogen Sensors Using Nitride-Based Semiconductor Diodes: The Role of Metal/Semiconductor Interfaces. Sensors 2011, 11, 674-695.
AMA StyleIrokawa Y. Hydrogen Sensors Using Nitride-Based Semiconductor Diodes: The Role of Metal/Semiconductor Interfaces. Sensors. 2011; 11(1):674-695.
Chicago/Turabian StyleIrokawa, Yoshihiro. 2011. "Hydrogen Sensors Using Nitride-Based Semiconductor Diodes: The Role of Metal/Semiconductor Interfaces." Sensors 11, no. 1: 674-695.


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The Spencer County Bears fell for the eighth consecutive game Friday night, losing to district foe North Oldham 42-32 in a game that saw plenty of bright spots for the Bears, but once again, too many mistakes.
Three turnovers gave the visiting Mustangs too many extra scoring opportunities and the Bears are now looking at just two games remaining on their schedule to avoid a winless season.
I've always wondered about the people who run for an elected office in our government. What fuels their desire to want to go through the battle of an election and then their time in office?
For many, I believe, it is an uncontrollable need to work for the people they serve and make things "right."
There's no ulterior motive, no selfish need for power, only the drive to help other people.
Two autumns ago, Michael Hartline was a quarterback who "we hope can manage a game," said UK offensive coordinator Joker Phillips.
A polite way of saying Hartline would have to do until Morgan Newton and/or Ryan Mossakowski were signed, suited up and tutored to handle SEC violence.
During the next two seasons the 6-6 kid from Ohio was adequate, streaks of pin-point passes checkered with spells of bumble-itis. Dropped passes and fickle fans didn't help.
I would like to personally thank everyone that worked so hard to make the Progressive Dinner such a success! Hats off to the volunteers for their tremendous effort.
Two local players were selected for the volleyball All District team. Junior Nikki Prater (left) and Senior Caitlyn Wolz were selected to the 11 player, 29th district, all-district team.
Pig Roast fundraiser at Pleasant Hill
Pleasant Hill Christian Church is hosting a pig roast fundraiser Oct. 23 to benefit the church's building fund.
The event will be from 1 p.m. until dark and will include special musical guests.
Pleasant Hill is located at the intersection of Highways 44 and 1579 between the Glensboro and Mount Eden communities.
For more information, call 502-220-6275.
Promiseland Pentecostal to host benefit gospel sing
The tricky details of Taylorsville's Halloween on Main Street have finally been decided.
The event's date—which has been under question for the past several weeks—has been determined by the Taylorsville City Commission as Oct. 30. Generally the yearly kid-friendly gathering is held Oct. 31 but the event's sponsors were forced to rethink the date after concerns were raised about Halloween falling on a Sunday this year.
Spencer County Preschool student Dawson Barr works on making hand print art Tuesday in Lisa Ingram's class. The AM and PM preschool classes made the hand prints in honor of grandparent's day, which the preschool is celebrating today and Thursday.
Working with military and veterans organizations, I have learned a great deal about leadership, dedication, integrity, and commitment. Words such as duty, respect, honor, courage, and selfless service define what these men and women represent.
What we need in our government today are men and women who not only believe in these qualities but live them.


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lasagna bolognese
This, this is my culinary Mount Everest. This twenty-layer striation of noodles, ragu, béchamel and cheese, repeated four times and then some took me more than five years to conquer. To be honest, six years ago I didn't know what it was. Sure, I had heard of lasagna but I wasn't terribly fond of it because I don't much care for the texture of ricotta once it has baked. (Ricotta, I'd argue, is best rich, fresh, and cold on toast.) But I was galloping through a post on an Italian food blog and I stumbled upon a parenthesised side-thought that stopped me dead in my tracks. It said something along the lines of "I don't know whose idea it was to put ricotta in lasagna but… shudder." And I thought, but wait! What's supposed to go in lasagna? But there was no answer, so I set out to find one.
Lasagna alla Bolognese is an epic dish. Oh sure, it looks like an ordinary broiled mass of cheese, pasta and meaty tomato sauce but it's so much more. To make it as I dreamed from that day forward I wanted to, everything gets a lot of love and time. The ragu is cooked for hours. The béchamel (ahem, besciamella), although the simplest of the five "Mother Sauces," is still a set of ingredients that must be cooked separately, and in a prescribed order. The pasta doesn't have to be fresh, but I figured if I was going to do this, I was going to really, really do this and I wanted fresh, delicious sheets of pasta to support the other cast members I'd so lovingly craft. And the cheese? There's just one, Parmesan, and it doesn't overwhelm.


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TOKYO (MarketWatch) -- Japanese shares edged higher Friday morning in Tokyo as trader cheered the latest financial results from major retailers. The Nikkei 225 Average was up 0.1% at 11,182 and the broader Topix added 0.1% to 986.65. Shares of Fast Retailing Co. Ltd. 9983, +0.74% FRCOF, +1.30% added 3.9% after the company reported on Thursday a 55.7% year-on-year rise in group net income for the first half of the fiscal year. Seven & I Holdings Co. 3382, +0.41% SVNDF, -1.97% added 4.8% after the company posted a 51.4% drop in net income for the fiscal year ended in February compared with a year ago, but said it expects to report a profit for the current fiscal year. Elsewhere, South Korea's Kospi was up less than 0.1% and Australia's S&P/ASX 200 was 0.4% higher.
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Transportation and Climate Change Clearinghouse
The Transportation and Climate Change Clearinghouse is designed as a one-stop source of information on transportation and climate change issues. It includes information on greenhouse gas (GHG) inventories, analytic methods and tools, GHG reduction strategies, potential impacts of climate change on transportation infrastructure, and approaches for integrating climate change considerations into transportation decision making.
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2014 DOT Climate Adaptation Plan
Pursuant to Executive Orders No. 13514 and 13653, as well as Council on Environmental Quality (CEQ) Implementing Instructions, the U.S. Department of Transportation (DOT) is required to submit a Climate Adaptation Plan. DOT's work on climate adaptation began with the understanding that climate impacts will affect DOT's strategic goals of safety, state of good repair and environmental sustainability. This plan is an update from the 2012 DOT Climate Adaptation Plan, which includes the new requirements of E.O. 13653 and guidance from CEQ. It reflects FY2013 and FY2014 commitments as well as other DOT accomplishments.
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Townsend Public Library will have Sunday hours for the 2015 winter months. We will be open from 1:00pm-5:00pm starting on Sunday January 4 and running every Sunday through April 26. Thank you to our donors who together provided the Friends of the Library with funds to open on Sundays. If you have the opportunity, please be sure show your appreciation to these generous donors. March 8 Townsend Community Couples Club March 15 Friends of the Library Collection Jars March 22 Friends of the Library Collection Jars March 29 Townsend Amanda E. Dwight Entertainment Fund |
TO GET INSTRUCTIONS FOR FORMS 1040, 1040A and 1040EZ (and other tax documents) The IRS is not sending instruction books to libraries this year. Following are the three options you have for viewing/obtaining instructions:
IRS.gov/Forms - to view and download
IRS.gov/orderforms - to order tax products to be delivered by U.S. mail
1-800-829-3676 - to order tax products to be delivered by U.S. mail
Lynda.com is a web-based video subscription service that provides courses for learning the latest commercial software, creative and business skills. How does it Work? The Library's lynda.com subscription allows patrons access from library computers or your desktop, mobile and tablet devices. You will need your library card and your library card account PIN. What's Available? More than 3000+ courses with 129,942 video tutorials. Most tutorials last several hours but are broken into multiple chapters. Software like MS Word, Excel, or PowerPoint; Adobe Photoshop, Illustrator. Web design: Web graphics, Interactive Design, Prototyping and more. Social media and web publishing tools like Facebook, Twitter and Wordpress. Job Search Tools: with Resume design, Searching for Positions, Working with Recruiters and more. Courses for all levels cover technical skills, creative techniques, business strategies, and more. Courses may also include exercise files (practice), closed captioning and text transcripts. You will be asked to create a LyndaLibrary account, which will allow you to track your progress through your tutorials. For Townsend Public Library cardholders only. |
Stitched With Love January 7th - February 28th, 2015
The Townsend Meeting Hall Art Gallery Committee invites you to view local artist's work using a variety of fiber;
whether it be fabric, thread, fleece, roving, yarn, or collage. Art Show ReceptionSaturday, February 14th @ 10 a.m. - 1 p.m.Artist demonstrations, Valentine's Day card making, and light refreshments. See the Meeting Hall Gallery page for more information about art shows in the gallery. |


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This is a backpacker's hostel in every sense of the word. It is cheap. It has a good location. Besides that I did not have a pleasant stay. There were not enough bathrooms for the amount of people staying. The bedrooms, bathrooms, shared rooms and kitchen were never in a clean condition. Do not expect to get any type of... More
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- TripAdvisor is proud to partner with HostelWorld, Booking.com, HostelBookers, Priceline and Odigeo so you can book your Lolo Urban House reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
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- Lolo Urban House Hotel San Sebastian - Donostia