New Medications & Those that have fallen from grace

New Medications & Those that have fallen from grace
J. Paul Martin, MD Asheville, NC

78 New Medications Approved in 2016 22 New Molecular Entities
8 First in Class 51 New Medications Approved in New Molecular Entities 20 First in Class 22New Molecular Entities in 2016 The 15 orphan NMEs constitute the highest total for these drugs since the passage of the Orphan Drug Act in 1983. drugs as first in a pharmacologic class New Medications

New Medications Cardiovascular Drugs Meds for Diabetes
Dermatologic Drugs Hepatitis Drugs Sleep Meds / Pain Meds Qsymia, Belviq, and Contrave all about $240/month. Sodium-glucose Co-transporter 2 inhibitor (SGLT2) – e.g. Invokana – off label

PCSK9 Inhibitors

Proprotein convertase subtilisin/kexin type 9
Enzyme that binds to the LDL Receptor in the liver and destroys the receptor and the LDL particle If PCSK9 does not bind, the receptor can return to the surface of the cell and remove more cholesterol PCSK9 inhibitors therefore increase the receptors available to lower the circulating LDL

PCSK9 Inhibitors Monoclonal Antibodies

PCSK9 Inhibitors Praluent - alirocumab Repatha – evolocumab
Alirocumab (trade name Praluent)[1] is a biopharmaceutical drug approved by the FDA in July 2015 as a second line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. It is a human monoclonal antibody that belongs to a novel class of anti-cholesterol drugs, known as PCSK9 inhibitors, and it was the first such agent to receive FDA approval. 75 mg SC q2 wks. Repatha approved in August It is produced using Chinese hamster ovary cells transfected with recombinant DNA, that are grown in tanks. 140 mg q2 wks. Amgen Wins Ban on Sanofi’s Praluent Cholesterol Drug Sales January 5, 2017, 4:46 PM EST January 5, 2017, 8:33 PM EST Judge issues order after upholding jury verdict Amgen won Ban takes effect in 30 days to give Sanofi time to appeal Amgen Inc. won a court ruling blocking rivals Sanofi and Regeneron Pharmaceuticals Inc. from selling their cholesterol-lowering drug Praluent in the U.S. because it infringes Amgen’s patents covering a rival treatment. U.S. District Judge Sue Robinson in Delaware ordered Sanofi and Regeneron Thursday to halt Praluent sales for 12 years because the drug infringes patents on Amgen’s Repatha medication. The order is a setback for the losing drugmakers since analysts expected Praluent to generate $2 billion in sales by 2020. Sanofi, Regeneron win a crucial stay of execution on Praluent February 8, :41 PM EDT Updated: 05:41 PM Sanofi and Regeneron’s Praluent gets to stay on the market while the partners fight another day in court for the PCSK9 franchise. Regeneron $REGN announced just after the market closed on Wednesday that the US Court of Appeals had granted a stay of a controversial decision in early January that Praluent violated Amgen’s patents on the rival PCSK9 cholesterol drug Repatha, warranting its removal from the market.

PCSK9 Inhibitors 60% decrease LDL when combined with statins
Unknown whether they decrease cardiovascular morbidity or mortality Cost - $14,600/year Treating all eligible patients - $80 Billion/yr The current treatment for people with very high cholesterol that cannot be controlled with diet or statins is apherisis, which is similar to dialysis in that a person visits a clinic each month and his or her blood is mechanically filtered, in this case to remove LDL cholesterol. That treatment costs $8000 per month, or $96,000 per year. The price of alirocumab was determined based in part on making apheresis no longer necessary.[21] ICER’s report also concludes that the two PCSK9 drugs appear to have equivalent overall effectiveness for most patient groups. The results of Institute for Clinical and Economic Review’s analyses indicate that the price that best represents the overall benefits these drugs may bring to patients would be between $3,615 and $4,811, representing a 67% discount off the list price. But, as Pearson noted, this price range excludes a critical consideration: potential budget impact. “Even if these drugs were used in just over 25% of eligible patients, then employers, insurers, and patients would need to spend on average more than $20 billion a year for these drugs, a cost that would continue on into the future.”

PCSK9 Inhibitors Manufacturer of Repatha (Amgen) sued Manufacturer of Praluent (Sanofi & Regeneron) for patent infringement 10/14. A jury found in favor of Repatha 3/16. 1/5/17Judge ordered Praluent off the US Market. Stay of execution by Appeals Court 2/8/17 The current treatment for people with very high cholesterol that cannot be controlled with diet or statins is apherisis, which is similar to dialysis in that a person visits a clinic each month and his or her blood is mechanically filtered, in this case to remove LDL cholesterol. That treatment costs $8000 per month, or $96,000 per year. The price of alirocumab was determined based in part on making apheresis no longer necessary.[21]

Diabetes HgbA1c > 6.5% or FBS > 126mg/dL
Sept 8,2015 JAMA – 12-14% Type 2 DM HgbA1c 5.7% - 6.4% Sept 8, 2015 JAMA – 38% with PreDiabetes Metformin – Glucophage, Glumetza; No weight gain; some experience weight loss. Some risk of hypoglycemia. Glipizide – Glucatrol; glimepiride – Amaryl; Associated with weight gain. A 2014 Cocharan review tentative evidence of fewer nonfatal CV events than metformin Repaglinide – Prandin, Nateglinide – Starlix; Acarbose – Precose, Miglitol – Glyset; Thiazolidinedione – pioglitazone-Actos; Rosiglitazone-Avandia . Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer.[4]

Diabetes Meds Insulin* Biguanides (metformin)*
Sulfonylureas (glipizide, glimepiride)* TZDs (pioglitazone, rosiglitazone) Meglitinides (repaglinide,nateglinide)* Metformin – Glucophage, Glumetza; No weight gain; some experience weight loss. Some risk of hypoglycemia. Glipizide – Glucatrol; glimepiride – Amaryl; Associated with weight gain. A 2014 Cocharan review tentative evidence of fewer nonfatal CV events than metformin Repaglinide – Prandin, Nateglinide – Starlix; Acarbose – Precose, Miglitol – Glyset; Thiazolidinedione – pioglitazone-Actos; Rosiglitazone-Avandia . Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer.[4] Rezulin (troglitazone) was pulled from market due to liver failure *May cause hypoglycemia

Diabetes Meds Alpha-Glucosidase Inhibitors (miglitol, acarbose)
Dopamine Agonist (bromocriptine)* Pramlintide (SymlinPen)* GLP-1 agonists (exenatide, liraglutide) DPP4 Inhibitors (sitagliptin) SGLT-2 Inhibitors (canagliflozin) Acarbose – Precose, Miglitol – Glyset; Cycloset Bromocriptine (quick release) recommended dose is 1.6 mg to 4.8 mg, administered once daily, within two hours after waking in the morning. It should be taken with food to potentially reduce the gastrointestinal side effects such as nausea. Bromocriptine mesylate should be initiated at one tablet (0.8 mg) ($2/pill) and increased by one tablet per week until a maximum daily dose of six tablets (4.8 mg) or until the maximal tolerated number of tablets, between two and six per day, is reached SymlinPen delays the time it takes the stomach to empty. It reduces glucagon secretion after meals and reduces appetite through a central mechanism. It is used before meals. It can cause hypoglycemia. It has been approved for use in Type 1 and Type 2 diabetes. Exenatide – Byetta/Bydureon; Liraglutide – Victoza; Study: Adding liraglutide to insulin not effective in type 1 diabetes Danish researchers found patients with poorly controlled type 1 diabetes had a nonsignificant -0.6% change in HbA1C levels from baseline to 12 weeks after adding once-daily liraglutide 1.2 mg to insulin, compared with -0.5% among those with a placebo add-on. The findings in Diabetes Care, based on 40 patients ages 18 to 70 with diabetes and a body mass index of 18 to 28, also showed 90% of those on liraglutide and 65% of those on placebo experienced adverse events, most of which were gastrointestinal. SOURCE: Diabetes Care 2015 Sitagliptin – Januvia Canagliflozin – Invokana

New Long-Acting Insulins
Lantus (insulin glargine) – now generic - “Biosimilars” –”Follow on” Toujeo (insulin glargine) 300U/ml Tresiba (insulin degludec) 100U/ml,200U/ml Sanofi makes Lantus and Toujeo Novo Nordisk makes Tresiba

Biosimilars Biologic medical product which is a copy of any original product manufactured by a different company, when the original product’s patent expires. E.g. monoclonal antibodies Biologics are genetically-engineered proteins derived from human genes. To be eligible for biosimilar status the original product has to be registered under the Public Health Service Act as the reference product

Lantus and biosimilars Insulin glargine
Lantus (insulin glargine) –off patent 2015 “Biosimilar” insulin glargine (Basaglar) Lantus went off pattent in The FDA approved Basaglar, but Sanofi sued Lilly for patent infringement. The applicant demonstrated that Basaglar was sufficiently similar to Lantus to scientifically justify reliance, and also provided Basaglar-specific data to establish the drug’s safety and efficacy for its approved uses. The Basaglar-specific data included two clinical trials enrolling 534 and 744 patients with type 1 and 2 diabetes mellitus respectively. No insulin glargine products are currently licensed under the Public Health Service Act, so there is no “reference product” for a proposed biosimilar product. Basaglar is manufactured by Eli Lilly and Company in Indianapolis, Indiana. Basaglar is manufactured by Eli Lilly and Company in Indianapolis, Indiana. Lilly ($LLY) agreed to pay royalties to Sanofi ($SNY) in exchange for a patent license. Lilly also pledged to wait to sell its pen-packaged biosimilar version of Lantus until December 15, 2016.

Lantus and biosimilars Insulin glargine
Lantus (insulin glargine) –$400 (5 Pens of 3 ml) “Biosimilar” insulin glargine (Basaglar) -$316.85 Lantus went off pattent in The FDA approved Basaglar, but Sanofi sued Lilly for patent infringement. The applicant demonstrated that Basaglar was sufficiently similar to Lantus to scientifically justify reliance, and also provided Basaglar-specific data to establish the drug’s safety and efficacy for its approved uses. The Basaglar-specific data included two clinical trials enrolling 534 and 744 patients with type 1 and 2 diabetes mellitus respectively. No insulin glargine products are currently licensed under the Public Health Service Act, so there is no “reference product” for a proposed biosimilar product. Basaglar is manufactured by Eli Lilly and Company in Indianapolis, Indiana. Basaglar is manufactured by Eli Lilly and Company in Indianapolis, Indiana. Lilly ($LLY) agreed to pay royalties to Sanofi ($SNY) in exchange for a patent license. Lilly also pledged to wait to sell its pen-packaged biosimilar version of Lantus until December 15, 2016.

Toujeo vs Lantus Both insulin glargine Both made by Sanofi

Toujeo (Insulin glargine
ml pens - $360 (1350 Units) Conversion rate Lantus : Toujeo : 1.1 Sanofi makes Lantus and Toujeo Novo Nordisk makes Tresiba Toujeo conversion -

Tresiba Insulin deglutec
Two doses (100Units/ml, 200Units/ml) 42 hour duration Flexible daily dosing – between 8 and 36 hrs Novo Nordisk Max dose 100Units/ml = 80U Units/ml = 160U Keeps for 8 weeks unrefrigerated….less waste

Tresiba Insulin deglutec
5 – 3ml pens - $464 / $555 Not available in Germany due to high pricing Novo Nordisk

Lantus (insulin glargine) – $400 Basaglar (insulin glargine) - $317 Toujeo (insulin glargine) 300U/ml - $360 Tresiba (insulin degludec) 100U/ml,200U/ml $464 $555 Sanofi makes Lantus and Toujeo Novo Nordisk makes Tresiba

Bernie Sanders asks DOJ & FTC to investigate insulin price fixing 11/3/16
Eli Lilly, Sanfi and Norvo Nodisk –simultaneous price increases 13 times since Cost of insulin triple from $231 - $736/patient/yr. Eli Lilly disagrees with accusations and pointed to the “complex reimbursement designs” which place an unfair burden on people with diabetes. Lilly complies with the law. Rebates

ACP Recommendations Oral Meds of Type 2 DM
that clinicians prescribe metformin to patients with type 2 diabetes when pharmacologic therapy is needed to improve glycemic control. (Grade: strong recommendation; moderate-quality evidence) that clinicians consider adding either a sulfonylurea, a thiazolidinedione, an SGLT-2 inhibitor, or a DPP-4 inhibitor to metformin to improve glycemic control when a second oral therapy is considered. (Grade: weak recommendation; moderate-quality evidence.) ACP recommends that clinicians and patients select among medications after discussing beneﬁts, adverse effects, and costs. Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on oral pharmacologic treatment of type 2 diabetes in adults. This guideline serves as an update to the 2012 ACP guideline on the same topic. This guideline is endorsed by the American Academy of Family Physicians. This article was published at on 3 January 2017.

Metformin New FDA Guidelines
Do not use if eGFR<30mL/min/1.73min/1.73m2 If already taking OK if >30 <45 OK for anyone with eGFR > 45 If eGFR > 60 OK to do venous/oral dye study and continue metformin Announced 4/8/16 For eGFR< 60 or with intraarterial dye studies stop the metformin before the patient undergoes the dye study and recheck in 48 hours to make sure that the eGFR is still in the safe range.

Metformin $4 60

Metformin New Research
Anti-inflammatory & antioxidant Reduced neuroinflammation Animal models – decreased pain hypersensitivity /cold allodynia with neuropathic pain Protective effect on neurodegeneration CV Benefit & Metabolic benefit in Type 1? Other recent reports provide a rationale as to why metformin should have a key role in chronic pain states particularly those that have centralized and have neuroinflammation Insulin has a direct effect on CNS mitochondria. Glial cells actively absorb glucose from the blood supply that feed the CNS. Metformin crosses the blood-brain barrier and apparently has a regulatory and homeostatic effect on glial cells and neuroinflammation.

Sulfonylureas 1st Gen – chlorpropamide, tolbutamide
2nd Gen - glipizide, glyburide 3rd Gen - glimepiride Hypoglycemia, renal impairment, weight gain Chlorpropamide – Diabenese, Tolbutamide – Orinase Glipizide – Glucatrol Glyburide – Micronase Sulfonylureas, the first drug group introduced into the U.S. in 1955, stimulates the beta cells to produce more insulin. Glipizide – Glucatrol; glimepiride – Amaryl; Associated with weight gain. A 2014 Cocharan review tentative evidence of fewer nonfatal CV events than metformin 1st Gens can bind to proteins and subsequently be dislodged by other meds leading to hypoglycemia. *May cause hypoglycemia

Sulfonylureas 1st Gen – chlorpropamide, tolbutamide $4
2nd Gen - glipizide, glyburide $4 3rd Gen – glimepiride $4 Hypoglycemia, renal impairment, lactic acidosis Chlorpropamide – Diabenese, Tolbutamide – Orinase Glipizide – Glucatrol Glyburide – Micronase Sulfonylureas, the first drug group introduced into the U.S. in 1955, stimulates the beta cells to produce more insulin. Glipizide – Glucatrol; glimepiride – Amaryl; Associated with weight gain. A 2014 Cocharan review tentative evidence of fewer nonfatal CV events than metformin 1st Gens can bind to proteins and subsequently be dislodged by other meds leading to hypoglycemia. *May cause hypoglycemia

Thiazolidinediones – TZDs No Hypoglycemia
Pioglitazone ( Actos) Rosiglitazone (Avandia) Troglitazone (Rezulin) Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis. Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer.[4] In Dec 2016 FDAwarned that pioglitazone containing meds may be linked to an increased risk of bladder cancer. Labels already contain warning. “Health care professionals should not use pioglitazone in patients with active bladder cancer and should carefully consider the benefits and risks before using in a patient with a history of bladder cancer. Rosiglitazone (Avandia), which was put under selling restrictions in the US and withdrawn from the market in Europe due to some studies suggesting an increased risk of cardiovascular events. Upon re-evaluation of new data in 2013, the FDA lifted the restrictions.

Thiazolidinediones - TZDs
Can Exacerbate CHF December 2016 – Bladder Cancer Warning reiterated by FDA Caution with liver disease Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis. Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer.[4] In Dec 2016 FDAwarned that pioglitazone containing meds may be linked to an increased risk of bladder cancer. Labels already contain warning. “Health care professionals should not use pioglitazone in patients with active bladder cancer and should carefully consider the benefits and risks before using in a patient with a history of bladder cancer. Rosiglitazone (Avandia), which was put under selling restrictions in the US and withdrawn from the market in Europe due to some studies suggesting an increased risk of cardiovascular events. Upon re-evaluation of new data in 2013, the FDA lifted the restrictions.

Thiazolidinediones Pioglitazone ( Actos) $17 (generic)
Rosiglitazone (Avandia) $174 (no generic) Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis. Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer.[4] Rosiglitazone (Avandia), which was put under selling restrictions in the US and withdrawn from the market in Europe due to some studies suggesting an increased risk of cardiovascular events. Upon re-evaluation of new data in 2013, the FDA lifted the restrictions.

Pioglitazone - generic www.goodrx.com 30mg (30 ea)
SamsClub – free Target (CVS) - $17 CVS - $169 Actos Brand - $692 Troglitazone (Rezulin), which was withdrawn from the market due to an increased incidence of drug-induced hepatitis. Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer.[4] Rosiglitazone (Avandia), which was put under selling restrictions in the US and withdrawn from the market in Europe due to some studies suggesting an increased risk of cardiovascular events. Upon re-evaluation of new data in 2013, the FDA lifted the restrictions.

GLP-1 Agonists/DPP4-I Glucose
Glucagon Like Peptide – 1 is an incretin GLP1 agonist. – (eg dulaglutide weekly) Dipeptidyl petidase – 4 Inhibitors (Januvia, Onglyza, tradjenta, Nesina) GLP-1 secretion by ileal L cells is dependent on the presence of nutrients in the lumen of the small intestine. The secretagogues (agents that cause or stimulate secretion) of this hormone include major nutrients like carbohydrate, protein and lipid. Once in the circulation, GLP-1 has a half-life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4. It is a potent antihyperglycemic hormone, inducing glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion. Such glucose-dependent action is particularly attractive because, when the plasma glucose concentration is in the normal fasting range, GLP-1 no longer stimulates insulin to cause hypoglycemia.

GLP-1 Agonists/DPP4-I Byetta Victoza Glucose Bydureon Tanzeum Tulicity
Glucagon Like Peptide – 1 is an incretin GLP1 agonist. – (eg dulaglutide weekly) Dipeptidyl petidase – 4 Inhibitors (Januvia, Onglyza, tradjenta, Nesina) GLP-1 secretion by ileal L cells is dependent on the presence of nutrients in the lumen of the small intestine. The secretagogues (agents that cause or stimulate secretion) of this hormone include major nutrients like carbohydrate, protein and lipid. Once in the circulation, GLP-1 has a half-life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4. It is a potent antihyperglycemic hormone, inducing glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion. Such glucose-dependent action is particularly attractive because, when the plasma glucose concentration is in the normal fasting range, GLP-1 no longer stimulates insulin to cause hypoglycemia. Januvia Nesina Onglyza Trajenta

GLP-1 Agonists subcutaneous injection No hypoglycemia Weight loss
CV benefit (13% fewer CV events)

GLP-1 Agonists subcutaneous injection
HA, N,V,D, Pancreatitis Thyroid tumors

DPP4 Inhibitors No hypoglycemia Weight Loss Januvia Nesina Onglyza
Trajenta DPP4 Inhibitors No hypoglycemia Weight Loss

GLP-1 Agonists subcutaneous injection
Byetta (exenatide) - $700 Victoza (liraglutide) - $780 Bydureon (exenatide) - $660 Tanzeum (albiglutide) - $500 Trulicity (dulaglutide) - $650

DPP4 Inhibitors Januvia (sitagliptin) - $400
Onglyza (saxagliptin) - $400 Tradjenta (linagliptin) - $400 Nesina (alogliptin) - $400 2014 meta analysis found no favorable or harmful effect of DPP-4 inhibitors on all-cause mortality, cardiovascular mortality, or stroke, but a marginally statistically significant increase in heart failure.[5]

SGLT-2 Inhibitors canagliflozin (Invokana) Dapagliflozin (Farxiga)
Empagliflozin (Jardiance) Cycloset Bromocriptine (quick release) recommended dose is 1.6 mg to 4.8 mg, administered once daily, within two hours after waking in the morning. It should be taken with food to potentially reduce the gastrointestinal side effects such as nausea. Bromocriptine mesylate should be initiated at one tablet (0.8 mg) ($2/pill) and increased by one tablet per week until a maximum daily dose of six tablets (4.8 mg) or until the maximal tolerated number of tablets, between two and six per day, is reached SymlinPen delays the time it takes the stomach to empty. It reduces glucagon secretion after meals and reduces appetite through a central mechanism. It is used before meals. It can cause hypoglycemia. It has been approved for use in Type 1 and Type 2 diabetes. Exenatide – Byetta/Bydureon; Liraglutide – Victoza; Study: Adding liraglutide to insulin not effective in type 1 diabetes Danish researchers found patients with poorly controlled type 1 diabetes had a nonsignificant -0.6% change in HbA1C levels from baseline to 12 weeks after adding once-daily liraglutide 1.2 mg to insulin, compared with -0.5% among those with a placebo add-on. The findings in Diabetes Care, based on 40 patients ages 18 to 70 with diabetes and a body mass index of 18 to 28, also showed 90% of those on liraglutide and 65% of those on placebo experienced adverse events, most of which were gastrointestinal. SOURCE: Diabetes Care 2015 Sitagliptin – Januvia Canagliflozin – Invokana

SGLT-2 Inhibitors The low-affinity sodium glucose transporter SGLT2, a protein expressed almost exclusively in the proximal tubule of the kidney, is a key player (Figure). SGLT2 mediates approximately 90% of active renal glucose reabsorption. SGLT1 has a secondary role to SGLT2. This transport process is saturated at high blood-glucose levels. In the presence of normal fluid volume status and kidney excretory function, glycosuria largely compensates for high levels of excessive glucose. Glucose appears in the urine at a rate linear with the filtered load.

Empagliflozin Jardiance
“Cuts CV Deaths” EMPA-REG Trial 5.9% placebo vs 3.7% Empagliflozin (37%) No decrease in stroke or MI Probably from its effect as osmotic diuretic decreasing incidence of CHF 63% lost>5% BW vs 27% on placebo 33% lost >10% BW vs 10% placebo In addition, GLP-1 inhibits gastric secretion and motility. This delays and protracts carbohydrate absorption and contributes to a satiating effect. Glucagon-like peptide-1 (GLP-1) is an incretin. The major source of GLP-1 in the body is the intestinal L cell that secretes GLP-1 as a gut hormone. GLP-1 secretion by ileal L cells is dependent on the presence of nutrients in the lumen of the small intestine. The secretagogues (agents that cause or stimulate secretion) of this hormone include major nutrients like carbohydrate, protein and lipid. Once in the circulation, GLP-1 has a half-life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4. It is a potent antihyperglycemic hormone, inducing glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion. Such glucose-dependent action is particularly attractive because, when the plasma glucose concentration is in the normal fasting range, GLP-1 no longer stimulates insulin to cause hypoglycemia.

Combination meds Synjardy is a combination of empagliflozin (Jardiance) and metformin used to help control blood glucose in patients with T2D. Empagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor, which reduces reabsorption of filtered glucose in the kidney thereby increasing urinary excretion of glucose and decreasing plasma glucose concentrations. Metformin acts to lower plasma glucose levels by decreasing its production in the liver as well as decreasing its absorption in the intestine. Linagliptin – Trajenta

Effects on HgbA1c Insulin – 3.5% Metformin – 1% Sulfonylureas – 1.25%
TZDs % GLP1 – 1–1.5% DPP4 Inhibitors 0.75% SGLT2 I– 0.5 – 1% FDA has approved a new once-daily, long-acting basal insulin, Toujeo (insulin glargine [rDNA origin] injection, 300 U/mL, Sanofi) for the treatment of adults with type 1 and type 2 diabetes mellitus. It is described as a more potent follow-up to the manufacturer’s insulin product Lantus (insulin glargine [rDNA origin] injection, 100 U/mL). It also has been designed to more gradually release the insulin – onset 6h, no true peak, duration hours. Tresiba supposedly acts for 48 hours. Germany felt no additional benefit and will not allow distribution in Germany. Novo Nordisk resubmitted new drug application in US saying it will complete required trial in second half of 2016. PHARMACIST’S LETTER / PRESCRIBER’S LETTER June 2015 Drugs for Type 2 Diabetes (Last modified September 2016) Diabetes Care 2010 Aug; 33(8):

Diabetes Meds Insulin* $275 - $464 Biguanides (metformin)* $4
Sulfonylureas (glipizide, glimepiride)* $4 TZDs (pioglitazone, rosiglitazone) $0- $17 Meglitinides (repaglinide,nateglinide)* $30-$219 Metformin – Glucophage, Glumetza; No weight gain; some experience weight loss. Some risk of hypoglycemia. Glipizide – Glucatrol; glimepiride – Amaryl; Associated with weight gain. A 2014 Cocharan review tentative evidence of fewer nonfatal CV events than metformin Repaglinide – Prandin, Nateglinide – Starlix; Acarbose – Precose, Miglitol – Glyset; Thiazolidinedione – pioglitazone-Actos; Rosiglitazone-Avandia . Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer.[4] Rezulin (troglitazone) was pulled from market due to liver failure *May cause hypoglycemia

Diabetes Meds Alpha-Glucosidase Inhibitors - $85
Dopamine Agonist (bromocriptine)* $360 Pramlintide (SymlinPen)* $860 GLP-1 agonists (exenatide, liraglutide) $600 DPP4 Inhibitors (sitagliptin) $400 SGLT-2 Inhibitors (canagliflozin) - $420 Cycloset Bromocriptine (quick release) recommended dose is 1.6 mg to 4.8 mg, administered once daily, within two hours after waking in the morning. It should be taken with food to potentially reduce the gastrointestinal side effects such as nausea. Bromocriptine mesylate should be initiated at one tablet (0.8 mg) ($2/pill) and increased by one tablet per week until a maximum daily dose of six tablets (4.8 mg) or until the maximal tolerated number of tablets, between two and six per day, is reached SymlinPen delays the time it takes the stomach to empty. It reduces glucagon secretion after meals and reduces appetite through a central mechanism. It is used before meals. It can cause hypoglycemia. It has been approved for use in Type 1 and Type 2 diabetes. Exenatide – Byetta/Bydureon; Liraglutide – Victoza; Study: Adding liraglutide to insulin not effective in type 1 diabetes Danish researchers found patients with poorly controlled type 1 diabetes had a nonsignificant -0.6% change in HbA1C levels from baseline to 12 weeks after adding once-daily liraglutide 1.2 mg to insulin, compared with -0.5% among those with a placebo add-on. The findings in Diabetes Care, based on 40 patients ages 18 to 70 with diabetes and a body mass index of 18 to 28, also showed 90% of those on liraglutide and 65% of those on placebo experienced adverse events, most of which were gastrointestinal. SOURCE: Diabetes Care 2015 Sitagliptin – Januvia Canagliflozin – Invokana

Eucrisa - crisaborole The US Food and Drug Administration (FDA) has approved crisaborole (Eucrisa, Pfizer Inc) for the treatment of mild to moderate atopic dermatitis (eczema) in patients aged 2 years and older. PDE-4 Inhibitor increases intracellular cyclic AMP

Mild to Moderate Atopic Dermatitis
$600 for 60 gram tube

Hepatitis C Six known Genotypes Genotype 1 – 75% of cases in US
A. GT 1a – 50% B. GT 1 b 25% GT2 a,b,c,d GT3 a,b,c,d,e,f GT4 a,b,c,d,e,f,g,h,i,j GT5 a GT6 a Approximately 75 percent of Americans with HCV have genotype 1; percent have genotypes 2 or 3; and a small numbers of patients are infected with genotypes 4, 5 or 6. According to the Centers for Disease Control and Prevention, HCV infection becomes chronic in approximately 75 to 85 percent of cases.

Hepatitis C Meds http://www.hcvguidelines.org/full-report-view
Medicare spent $9.2 Billion on Hepatitis C treatment in 2015 up 96% from 2014 $4.7 Billion.

Harvoni Ledipasvir/sofosbuvir
Hepatitis C genotype 1 – 94% clearing of virus 12-week-course $96,000 1 tab daily No interferon or ribavirin 24-week-course for prior treatment failure Ledipasvir is a NS5A Protease inhibitor Approved for genotypes 4,5,6 in Nov 2015 FDA approved October 10, 1014 Genotype 1 HCV infection accounts for approximately 75% of chronic HCV cases in the United States (US) Replication involves the RNA genome creating a polyprotein sequence of ~3,000 amino acids. Viral and host enzymes then cleave the polyprotein into viral proteins (structural and non-structural) and enzymes providing the necessary components for subsequent viral replication and virion assembly. Ledipasvir is an inhibitor of the hepatitis C virus NS5A protein. Non-structural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) are cleaved from the polyprotein by HCV-encoded proteases (NS2/3 autoprotease, NS3/4 serine protease, NS3 helicase, and NS5B RNA dependent RNA polymerase) and are essential for viral replication.

Viekira Pak ombitasvir/paritaprevir/ritonavir/dasabuvir
Hepatitis C genotype 1 > 90% week-course Tablets BID – Blister Pack Patients with GT 1a, cirrhosis or liver transplant also receive ribavirin 24-week-course for GT1a w cirrhosis $85,500 for 12 week course FDA warning about liver damage FDA approved December 19, 1014 Genotype 1 HCV infection accounts for approximately 75% of chronic HCV cases in the United States (US) Ritonavir is a P-glycoprotein inhibitor and blocks the pump to clear the other drugs from the cell. Many patients getting Viekira also have to take ribavirin, an older drug that can have serious side effects.Ribavirin is $5000 for 12 week course Express Scripts

3 Million Americans with Hepatitis C
Cost for treating all with Harvoni = $282,000,000,000 Gilead announced Solvaldi would be discounted up to 46% on the average

Hepatitis C Meds Epclusa (sofosbuvir and velpatasvir)
Given with Ribavirin ($600) Treats all six types of Hepatitis C $75,000 for 12 week course The safety and efficacy of Epclusa for 12 weeks was evaluated in three Phase III clinical trials of 1,558 subjects without cirrhosis or with compensated cirrhosis (mild cirrhosis). Results demonstrated that 95–99 percent of patients who received Epclusa had no virus detected in the blood 12 weeks after finishing treatment, suggesting the patients’ infections had been cured. The safety and efficacy of Epclusa was also evaluated in a clinical trial of 267 subjects with decompensated cirrhosis (moderate to severe cirrhosis), of whom 87 subjects received Epclusa in combination with ribavirin for 12 weeks, and 94 percent of these patients had no virus detected in the blood 12 weeks after finishing treatment.

(sofosbuvir)

New Hepatitis Medications
Pause for a moment The 15 orphan NMEs constitute the highest total for these drugs since the passage of the Orphan Drug Act in 1983. 2014 Medicaid spent 4.5 Billion on the new hepatitis meds 19,600 deaths from Hepatitis C in 2014 New Hepatitis Medications

Movantik (naloxegol) CII
Once a day oral tablet - $9 Opioid – induced constipation “Peripherally” acting mu-opioid receptor antagonist 25mg 1 hour before meal CYP 3A4 inhibitors increase risk of withdrawal Naloxegol is a PEGylated derivative of naloxone, and is a substrate for the P-glycoprotein transporter (P-gp). Also, the presence of the PEG moiety in naloxegol reduces its passive permeability as compared with naloxone. Due to the reduced permeability and increased efflux of naloxegol across the blood-brain barrier, related to P-gp substrate properties, the CNS penetration of naloxegol is expected to be negligible at the recommended dose levels limiting the potential for interference with centrally mediated opioid analgesia. •Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning, occurred in patients treated with MOVANTIK. Patients receiving methadone in the clinical trials were observed to have a higher frequency of GI adverse reactions that may have been related to opioid withdrawal than patients receiving other opioids. Patients with disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Monitor for symptoms of opioid withdrawal when using MOVANTIK in such patients ◦Patients receiving strong CYP3A4 inhibitors (eg, clarithromycin, ketoconazole) because these medications can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms Relistor – methylnaltrexone is injectable 12 mg SC daily

Fallen Angels Diabetes meds Codeine Discontinued by manufacturer

Previous “angels” Darvocet, Vioxx, Cylert, Accutane, Baycol, Bextra, Hismanol, Diethylstilbesterol

Proton Pump Inhibitors
Linked to 20% increased incidence of stroke (not causal!) Increased risk of Clostridium difficile Increased risk of Osteoporosis/Bone Fractures PPI associated Pneumonia? Increased risk of dementia? 1.PPIs reduce production of nitric oxide leading to endothelial dysfunction Danish nationwide observational study presented at AHA 2016 Scientific Sessions: Stroke – Observational study, not causal; no increased risk with histamine-2 blockers Other biologically plausible side effects including B12/magnesium/iron deficiencies, gastric carcinoid, interstitial nephritis – not shown in clinical studies. 2. Travelers Diarrhea: The International Society of Travel Medicine, however, does suggest discontinuing PPIs if traveling to areas with risk of enteric infection.[61] This seems reasonable if patient risk assessment is individualized and, when possible, PPIs can be stopped for a short period of time without other GI consequences. 3. Block absorption of Calcium Carbonate – use calcium citrate n 2010 the FDA issued a product label warning for all PPIs because of clinical reports inferring increased risk for bone fractures. The FDA revised this warning in March of 2011 to release over-the-counter PPIs, which are intended for short-term use (ie, 2 weeks) for up to 3 cycles per year.[10] Proton pump inhibitors (PPIs) are the third highest-selling drug in the United States PPIs may interfere with the metabolism of clopidogrel (Plavix). The latest concern is that PPIs might increase the risk for dementia. Britta Haenisch and colleagues at the German Center for Neurodegenerative Diseases in Bonn studied 73,679 people ages 75 and older. The researchers found regular PPI users had at least a 44 percent increased risk of dementia compared with those not using the drugs.

Beta Blockers aka the “lols”
Propranolol (Inderal) Atenolol (Tenormin)* Metoprolol (Lopressor) Carvedilol (Coreg) Nebivolol (Bystolic) Prescribing Information INDICATION AND IMPORTANT SAFETY INFORMATION BYSTOLIC is indicated for the treatment of hypertension, to lower blood pressure. BYSTOLIC may be used alone or in combination with other antihypertensive agents. BYSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product. Indication and Important Safety Information continued below. BYSTOLIC: EFFECTIVE AS MONOTHERAPY IN ADULT PATIENTS <55 YEARS OF AGE Dear Paul Martin, MD, BYSTOLIC can be an effective choice for the treatment of hypertension. When starting therapy for appropriate new hypertensive patients, consider the data below, along with BYSTOLIC's low incidence of side effects in registration trials. The 5 most common adverse events with BYSTOLIC in monotherapy registration studies were headache, fatigue, dizziness, diarrhea, and nausea. See a healthcare professional review a trial of BYSTOLIC as a monotherapy in adult patients <55 years of age. In an 8-week study BYSTOLIC monotherapy provided significant blood pressure (BP) reductions in an adult patient population <55 years of age1 • Mean age for this study was 45.3 years1 Adverse events in this study of adult patients less than 55 years of age1 In an 8-week study of patients <55 years of age, the most common adverse events occurring in ≥1% of patients taking BYSTOLIC and more frequently than in patients taking placebo were upper respiratory tract infection (5.4% for BYSTOLIC vs 1.9% for placebo), peripheral edema (1.9% vs 0.5%), cough (1.6% vs 1.4%), arthralgia (1.2% vs 0.5%), bradycardia (1.2% vs 0%), bronchitis (1.2% vs 0.5%), diarrhea (1.2% vs 0.9%), and joint swelling (1.2% vs 0%).1 Please refer to the full Prescribing Information for the BYSTOLIC safety profile. In pooled results from three 3-month monotherapy registration studies, no overall differences in efficacy in younger vs older patients2,3 In these studies, younger patients were defined as adults 64 years of age or younger; older patients were defined as adults 65 years of age or older2 — Mean age in the monotherapy registration studies was 54 years2 Low incidence of side effects in registration trials The 5 most common adverse events with BYSTOLIC were headache, fatigue, dizziness, diarrhea, and nausea2 Discontinuation rate due to adverse events was 2.8% for BYSTOLIC vs 2.2% for placebo2 Please see full Important Safety Information below. Review trial of BYSTOLIC as a monotherapy in adult patients <55 years of age. Learn More. INDICATION BYSTOLIC is indicated for the treatment of hypertension, to lower blood pressure. BYSTOLIC may be used alone or in combination with other antihypertensive agents. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. There are no controlled trials demonstrating risk reduction with BYSTOLIC, but at least one pharmacologically similar drug has demonstrated such benefits. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. IMPORTANT SAFETY INFORMATION Contraindications BYSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product. Warnings and Precautions Do not abruptly discontinue BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction, and ventricular arrhythmias have been reported following the abrupt discontinuation of therapy with beta blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other beta blockers, when discontinuation of BYSTOLIC is planned, carefully observe and advise patients to minimize physical activity. Taper BYSTOLIC over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, restart BYSTOLIC promptly, at least temporarily. BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. In general, patients with bronchospastic diseases should not receive beta blockers. Because beta blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta blockers should generally continue treatment throughout the perioperative period if undergoing major surgery. If BYSTOLIC is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene are used. If beta-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The beta-blocking effects of BYSTOLIC can be reversed by beta agonists, eg, dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with beta blockers. Beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities. Beta blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta blockers in these patients may be followed by an exacerbation of symptoms or may precipitate a thyroid storm. Beta blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Because of significant negative inotropic and chronotropic effects in patients treated with beta blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure of patients treated concomitantly with these agents. When BYSTOLIC is co-administered with an inhibitor or an inducer of CYP2D6, monitor patients closely and adjust the nebivolol dose according to blood pressure response. The dose of BYSTOLIC may need to be reduced. When BYSTOLIC is administered with fluoxetine, significant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC and a 3-fold increase in Cmax for d-nebivolol). Renal clearance of nebivolol is decreased in patients with severe renal impairment. In patients with severe renal impairment (ClCr less than 30 mL/min) the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients receiving dialysis. Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients with severe hepatic impairment and therefore it is not recommended in that population. Patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine while taking beta blockers. In patients with known or suspected pheochromocytoma, initiate an alpha blocker prior to the use of any beta blocker. Adverse Reactions The most common adverse events with BYSTOLIC versus placebo (approximately ≥1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%), and bradycardia (0.2%). Drug Interactions Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc). Do not use BYSTOLIC with other beta blockers. Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. BYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide. Use in Specific Populations Use BYSTOLIC during pregnancy only if the potential benefit justifies the potential risk to the fetus. BYSTOLIC is not recommended during nursing. The safety and effectiveness of BYSTOLIC have not been established in pediatric patients. In a placebo-controlled trial of 2128 patients (1067 BYSTOLIC, 1061 placebo) over 70 years of age with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was reported with nebivolol compared to placebo. However, if heart failure worsens, consider discontinuation of BYSTOLIC. Please also see full Prescribing Information. References: 1. Giles TD, Khan BV, Lato J, Brener L, Ma Y, Lukic T. Nebivolol monotherapy in younger adults (younger than 55 years) with hypertension: a randomized, placebo-controlled trial. J Clin Hypertens (Greenwich). 2013;15: BYSTOLIC [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc. 3. Data on file. Forest Laboratories, LLC.

Medications – Beta Blockers
Cochrane Database Syst Rev 2007 RCTs assessing the effectiveness of beta blockers compared to placebo, no therapy or other drug classes, as monotherapy or first-line therapy for HTN, on morbidity and mortality endpoints 13 RCTs; 91,561 subjects Available evidence does not support the use of beta blockers as first-line agents in HTN treatment Atenolol – Tenormin Design, Setting, and Patients Longitudinal, observational study of patients in the Reduction of Atherothrombosis for Continued Health (REACH) registry who were divided into 3 cohorts: known prior MI (n = 14 043), known CAD without MI (n = 12 012), or those with CAD risk factors only (n = 18 653). Propensity score matching was used for the primary analyses. The last follow-up data collection was April 2009. Main Outcome Measures The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. The secondary outcome was the primary outcome plus hospitalization for atherothrombotic events or a revascularization procedure. Side effects: abradycardia, AV block, bronchospasm, hyperkalemia

Medications – Beta Blockers
JAMA Oct 3, ,000 patient observation – no lower risk of composite CV events with Beta Blockers even in patients s/p MI (distant) 2008 COMMIT Study 46,000 patients in China – no improved outcome with metoprolol in Acute MI Available evidence does not support the use of beta blockers as first-line agents in HTN treatment Atenolol = Tenormin Design, Setting, and Patients Longitudinal, observational study of patients in the Reduction of Atherothrombosis for Continued Health (REACH) registry who were divided into 3 cohorts: known prior MI (n = 14 043), known CAD without MI (n = 12 012), or those with CAD risk factors only (n = 18 653). Propensity score matching was used for the primary analyses. The last follow-up data collection was April 2009. Main Outcome Measures The primary outcome was a composite of cardiovascular death, nonfatal MI, or nonfatal stroke. The secondary outcome was the primary outcome plus hospitalization for atherothrombotic events or a revascularization procedure. Side effects: abradycardia, AV block, bronchospasm, hyperkalemia 2008 COMMIT Study 46,000 patients in China – no improved outcome with metoprolol in Acute MI

Beta Blockers aka the “lols”
Atenolol (Tenormin)* Should be given BID not qd!

Codeine Codeine, Morphine, Thebaine
Cytochrome P450 isoenzyme-2D6 (CYP2D6) Codeine is a prodrug, meaning that it has to be converted into its active form, morphine, for its analgesic effect to be fully realized. Cytochrome P450 isoenzyme-2D6 (CYP2D6) is responsible for its hepatic conversion, and of course this extra biotransformation step increases the chances for alterations in the extent and speed of the enzyme's conversion of codeine to morphine. There are considerably more drugs that inhibit CYP2D6 than accelerate it. Drugs that inhibit the CYP2D6 enzymatic process can decrease or even essentially block it, making codeine less effective or essentially ineffective. Fluoxetine (Prozac), paroxetine (Paxil), bupropion (Wellbutrin), and duloxetine (Cymbalta) are examples of drugs that can substantially inhibit CYP2D6 and thereby have the potential to reduce the efficacy of codeine. Alternatively, multiple doses of drugs such as dexamethasone and rifampin can increase the CYP2D6 conversion process, and this could increase the conversion of codeine into morphine such that higher than expected blood levels of morphine could develop fairly quickly, causing signs and symptoms of acute narcotic overdose.

Codeine Ultra-rapid Metabolizers FDA black box warning: no codeine for kids <12 judicious use in kids <18 Codeine, Morphine, Thebaine Ultrarapid metabolizers are found in about 1 percent of people from Finland and Denmark, about 4 percent in Caucasian North Americans, about 10 percent of people from Greece and Portugal, about 20 percent in Saudi Arabia and almost 30 percent of people from Ethiopia. In addition to drug interactions, other factors can modify the activity of CYP2D6 enzymes. CYP2D6 demonstrates the largest phenotypical variability among the various CYPs, primarily because of genetic polymorphism. Slow, intermediate, normal, and ultrarapid metabolizers have been discovered, depending on the genetic makeup of a patient's enzymes. The FDA has collected 13 reports of deaths of children between 1969 and 2012 who were prescribed codeine-containing products for postoperative pain. Most of these tragic events took place following tonsillectomy, and many of the children had OSA. Based perhaps on elevated levels of morphine in the blood compared to the dose of codeine prescribed, but not necessarily taking into account the amount actually given by the parent or caregiver, the FDA believed that there was evidence that some of these children were CPY2D6 ultrarapid metabolizers. However, since many of these children had OSA, they may simply have been more sensitive to the respiratory depressant effects of the elevated levels of morphine or more sensitive to a larger-than-prescribed dose actually given by the parent or caregiver.

Fallen Angels Beta blockers Codeine Discontinued by manufacturer

Farewell Old Friends Avinza (morphine sulfate)
Roxicet Oral Solution (oxycodone/tylenol) Phentolamine (reprieved) Pegintron / Rebetol Auralgan (antipyrin/benzocaine) Avinza 30,45,60,75,90, once a day, but NOT tamper resistant Roxicet tablets still available Phentolamine – alpha adrenergic blocker (Previous Regitine) Pegintron/Rebetol - Merck

Avinza Once a day oral tablet – but NOT tamper resistant

Effective Feb 1, 2016 Rebetol (ribavirin) capsules
Pegintron (peginterferon alfa-2b) Once-Weekly Peg-Intron (Peginterferon Alfa-2b) Injection Plus Daily Rebetrol (Ribavirin, USP) Capsules Shows Promise In Hepatitis C ATLANTA, GA -- May 24, Schering-Plough Research Institute today reported interim results of two ongoing investigational clinical studies with once-weekly Peg-Intron? (peginterferon alfa-2b) Injection plus daily Rebetrol? (Ribavirin, USP) Capsules in patients with chronic hepatitis C who did not respond to, or had relapsed following, previous interferon-based therapy. These data are being presented for the first time here at the 2001 Digestive Diseases Week (DDW) conference. Effective Feb 1, 2016

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New Medications & Those that have fallen from grace
J. Paul Martin, MD Asheville, NC

New Medications & Those that have fallen from grace

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