Pharmacy update What’s new in the world of pharmaceuticals? Petra Eichelsdoerfer, ND, CN, RPh New...

1

Pharmacy update

What’s new in the world of

pharmaceuticals?Petra Eichelsdoerfer, ND, CN, RPh

New Hampshire Association of Naturopathic Doctors

Fall Seminar, Nashua, NH

November 1, 2013

Disclosure

No potential conflict of interest

2

3

Learning Objectives

After attending this presentation, attendees will

• Be aware of new medications that may be useful for their patients

• Gain deeper awareness of how older medications may benefit, or harm, their patients

• Understand recent changes in medication treatment approaches for common medical conditions, including diabetes, hypertension, hyperlipidemias, and infectious diseases

4

Outline• Update on older medications, including

• Indications and contraindications• Drug interactions• Significant monitoring parameters

• New medications

• Update on medication treatments for conditions treated by NDs, including

• Diabetes• Hypertension• Hyperlipidemias• Infectious diseases

New Information on Older Medications

5

Opioids and Drugs of Abuse

The concern

• US prescription pain medication overdoses epidemic according to the Centers for Disease Control and Prevention (CDC)

• 100 Americans die each day from prescription drug overdoses

• 75% of these deaths involve opiates.

Centers for Disease Control and Prevention, www.cdc.gov 6

http://www.cdc.gov/

Prescription Drug Monitoring Programs (PMPs)

• Statewide electronic database of controlled substance prescriptions

• Intended to help the fraudulent obtaining of controlled substance prescriptions

• Implemented voluntary PMP 40 years ago• Data available to prescribers, law enforcement, licensing boards, patients• NOT pharmacists

• Internet System for Tracking Over-Prescribing (I-STOP) • Real-time tracking for Schedule II, III, & IV controlled substances• Requires prescribers to consult the registry before prescribing these, effective

August 2013• Requires all prescriptions for these be transmitted electronically to the

registry• Mandatory electronic prescribing of controlled substances will occur by

December 2014 • Exemptions for hospital use and directly administered medications

American Society of Health-System Pharmacy News, www.ashp.org 7

http://www.ashp.org/


• All states except Missouri have in operation or development

• Some supported by grants from the Substance Abuse and Mental Health Services Administration (SAMHSA)

• Wyoming is only state other than NY to collect data in real time

• Lag time allowed between dispensing and reporting varies from 24 hours to 30 days

• 24 hours: Delaware, Kansas, Kentucky, Minnesota, North Dakota, and West Virginia

• Alaska, Pennsylvania, Rhode Island, and South Carolina

• Maryland's PMP is scheduled to become fully operational late this year. American Society of Health-System Pharmacy News, www.ashp.org

8


9


• New Hampshire’s program remains under development• Information deleted from NH database after 6 months unless

suspicion of abuse. All other information deleted after 3 years• Police cannot access without court order• Jay Queenan, NH Board of Pharmacy Executive Director

• Phone: 603-271-7842; Email: [email protected]• http://www.nh.gov/pharmacy/prescription-monitoring/index.htm

• For more information• DEA

• http://www.deadiversion.usdoj.gov/faq/rx_monitor.htm

• Alliance of States with Prescription Monitoring Programs webpages:

• http://www.pmpalliance.org/

mailto:[email protected]

http://www.nh.gov/pharmacy/prescription-monitoring/index.htm

http://www.deadiversion.usdoj.gov/faq/rx_monitor.htm

http://www.pmpalliance.org/

What else is happening to help curb abuse & misuse of opioids?

• Drug Enforcement Administration (DEA) action against pharmacies

• Result: • Pharmacy chain reviewed prescriptions to identify clinicians who may have

prescribed excessive quantities of opioids• Pharmacy chain stopped filling prescriptions for opioid drugs from 36

clinicians.

• Scheduling or re-scheduling some drugs• Scheduling tramadol as C-IV• Re-scheduling hydrocodone as C-II

• Hydrocodone-containing products top sellers, 2007 - 2011• In 2011

• 131 million rxs for hydrocodone-containing products • 35 million rxs for (C-II) oxycodone-containing products

• Concerns• Addicted patients may turn to heroin and other street drugs• Treatment programs may not have capacity for increased patient load



Extended release & long-acting opioids: Label changes proposed

• Examples include: morphine, oxycodone, oxymorphone, fentanyl• Higher dose products, with long-lasting effects

• Current labeling indication: • For "the relief of moderate to severe pain in patients requiring continuous,

around-the-clock opioid treatment for an extended period of time."

• Updated labeling intended to emphasize need to consider that other, less potentially addictive, treatment options

• Indication: “for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate."

• Limitations of use section adds: • (These meds) not intended for use as an "as-needed" pain reliever • "Because of the risks of addiction, abuse and misuse with opioids, even at recommended

doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve [Tradename] for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain."

US Food and Drug Administration, www.fda.gov 11

http://www.fda.gov/

Codeine use in children• New contraindication added to codeine labeling: Not for use in

children post- tonsillectomy or adenoidectomy

• Recommendation: select a different analgesic for pain management post-tonsillectomy or adenoidectomy in children

• FDA panel states non-prescription analgesics and hydration can often adequately manage pain

• American Academy of Otolaryngology—Head and Neck Surgery suggests ibuprofen

• Based on reports for deaths or life-threatening respiratory failure in children with

• Obstructive sleep apnea syndrome, AND • CYP 2D6 isoform ultra-rapid codeine to morphine metabolism• Four additional children died or exhibited evidence of morphine overdose after

adenotonsillectomy

• Routine testing for CYP2D6 genotype not recommended for children undergoing tonsillectomy or adenoidectomy



Codeine metabolism

Crews, et al. Clinical Pharmacol Ther. 2012; 91: 321 - 32613

Zolpidem dose update• New pharmacokinetics data from driving-simulation studies

• Nighttime dose of zolpidem may impair AM driving• Occurs with all versions of zolpidem• More likely with extended-release products

• Dosing recommendations for women reduced by half • Women slower to eliminate zolpidem

• New recommendations for immediate release products: • Women: 5 mg taken once at bedtime. • Men: 5 or 10 mg taken once at bedtime.

• New recommendations for extended release products:• Women: 6.25 mg taken once at bedtime• Men: 6.25 or 12.5 mg taken once at bedtime

• Intermezzo (SL formulation) dosing already lower for women•

• Dosing may be increased if needed, but increases risk for next-morning impairment.



Benzodiazepines (BZDs)• Combining benzodiazepines generally NOT recommended

• Increased risk for sedation, memory loss, falls• Includes use of non-benzodiazepine hypnotics (e.g., zolpidem)• ALWAYS recommended to avoid other CNS depressants (e.g., alcohol)

• Logical situations where benzodiazepines may be combined• Different conditions – e.g., lorazepam for daytime anxiety, plus

temazepam at bedtime for sleep. • Long-acting plus occasional use of a shorter-acting BZD

• Alternatives to consider • If a sleep med is needed with a daytime benzodiazepine, consider

• Melatonin or ramelteon (Rozerem)• Low-dose trazodone or doxepin

• For anxiety, focus on optimizing dose of medium- or long-acting BZD (e.g., lorazepam, clonazepam)

• Consider tapering patients off BZDs when possiblePharmacist’s Letter, www.pharmacistsletter.com

15

http://www.pharmacistsletter.com/

16

Benzodiazepine discontinuation• Symptoms most likely with shorter-acting agents, longer

duration of use

• Onset within 1 – 10 days; duration, 5 days – 1 month

• Managing withdrawal• Decrease dose gradually over 4 to 8 weeks

• Consider switching patients on shorter-acting agents to longer-acting ones

• Adjunctive pharmaceutical therapies include clonidine, propranolol, carbamazepine

Source: Facts & Comparisons

Adapted from: Facts & Comparisons

Comparing benzodiazepines (sampling)

DrugDosage

range (mg/d)

Peak plasma level (h)

Elimination t1/2 (h) Metabolites

Speed of onset

Protein binding

Alprazolam 0.75 to 4 1 to 2 6.3 to 26.9 Active intermediate 80%

Chlordiazepoxide

15 to 100 0.5 to 4 5 to 30 Active intermediate 96%

Clonazepam 0.5 to 20 1 to 4 18 to 50 Inactive intermediate 85%

Clorazepate 15 to 60 1 to 2 40 to 50 Active fast 97% to 98%

Diazepam 4 to 40 0.5 to 2 20 to 80 Active very fast 98%

Lorazepam 2 to 4 2 to 4 10 to 20 Inactive intermediate 85%

Oxazepam 30 to 120 2 to 4 5 to 20 Inactive slow 87%

Temazepam 7.5 – 30 1.2 – 1.6 3.5 – 18.4 Inactive fast 96%

Triazolam 0.125 – 0.5 1 – 2 1.5 – 5.5 Inactive fast

17

Adverse Reactions, Interactions, and

Special Prescribing Situations

18

CYP 3A4 – Grapefruit interaction• Grapefruit Irreversible inactivation of GUT CYP3A4 enzymes

• 48 - 72 hours required to replace• Separating the ingestion of grapefruit from medication does NOT prevent interaction• 1 grapefruit or 200 ml (~7 fl oz) juice may clinically significant interaction• Over 85 interactions identified, ~ 50% may serious reactions

• Most likely to happen if • Drug has very low oral absorption due to CYP 3A4 metabolism• Small changes in enzyme activity may significant increase in absorption.

• Recently recognized interactions• Ticagrelor (Brilinta) Increased GI bleeding risk• Dronedarone (Multaq) Increased arrhythmia risk• eplerenone (Inspra) Increased hyperkalemia risk

• Recommendation:• Avoid grapefruit if taking an interacting med, or • Switch to an alternative less likely to interact• Example: Pravastatin and rosuvastatin do NOT interact with grapefruit , while atorvastatin ,

simvastatin and lovastatin DO

• What about other fruits? • Primary concern is dose• Limes , pomelos, and Seville sour oranges contain the interacting flavonoid• Lemons , sweet oranges do NOTPharmacists’s Letter, www.pharmacistsletter.com 19

P-glycoprotein interactions• AKA multidrug resistance protein 1 (MDR1)

• Now included in labeling due to new drug research requirements• Many interactions attributed to just CYP3A4 may also involve P-glycoprotein.

• Efflux pump found in gut, kidneys, liver, blood-brain barrier • Often works hand-in-hand with CYP, especially CYP3A4• Prevents absorption of xenobiotics into body (gut)• Helps eliminate xenobiotics from the body through bilie, urine • Prevents uptake of xenobiotics into brain (blood-brain barrier)• May activate in cancer cells, increasing their resistance to chemotherapeutic agents

• Drugs known to be transported by p-glycoprotein• Cyclosporine, digoxin, fexofenadine, paclitaxel, saquinavir, vinblastine

• Known p-glycoprotein inhibitors: • Clarithromycin, itraconazole, lopinavir, ritonavir, verapamil, grapefruit juice• Note: Inhibitors of CYP3A4 may also inhibit p-glycoprotein• May result in increased blood levels of p-glycoprotein substrate

• Known p-glycoprotein inducers• Carbamazepine, rifampin, Hypericum perforatum (St John’s Wort)• May result in reduced blood levels of p-glycoprotein substrate

Pharmacist’s Letter, www.pharmaicstsletter.com 20

http://www.pharmaicstsletter.com/

P-glycoprotein interactions• Newer meds list clinically significant interactions on label

• Rivaroxaban (Xarelto), apixaban (Eliquis), linagliptin (Tradjenta)

Examples with recommendations

• Digoxin (not a CYP3A4 substrate) interacts with known CYP3A4 inhibitors due to p-glycoprotein inhibition

• Clarithromycin + digoxin 12-fold increased risk hospitalization due to digoxin toxicity

• Dronedarone + digoxin increased risk of sudden death. • Recommendations for digoxin therapy with drugs altering p-glycoprotein

activity: • Reduce oral digoxin ~ 50% while on p-glycoprotein inhibitor, e.g., clarithromycin,

amiodarone, or dronedarone. • Increase oral digoxin ~ 30% while on inducers, e.g., rifampin, phenytoin, Hypericum

• Apixaban (Eliquis) – Recommendation• Reduce doses or avoid with drugs that inhibit both p-glycoprotein & CYP 3A4,

e.g., clarithromycin, itraconazole, etc. • Avoid combining with INDUCERS, e.g., rifampin, phenytoin, St. John's wort,

etc. • This also applies to rivaroxaban (Xarelto), dabigatran (Pradaxa)

Pharmacist’s Letter, www.pharmaicstsletter.com 21

http://www.pharmaicstsletter.com/

Organic anion transporting peptide (OATP) inhibition & interactions• Uptake transporter family (e.g., OATP1A2, OATP2B1)

• Enhance uptake into cells• Located in gut, liver, kidney, blood-brain barrier• Genetic polymorphisms influence activity level

• Inhibitors of OATP include: • Grapefruit, sweet oranges, apples• 200 – 600 ml of juice sufficient inhibition

• Effect of OATP inhibition decreased uptake by cells• Grapefruit effects may “balance out” if drug also metabolized by CYP 3A4

• Drugs affected by OATP inhibition include • Beta-blockers: Atenolol, acebutolol• Renin inhibitor: Aliskiren• Leukotriene receptor antagonist: Montelukast• Fluoroquinolones: Ciprofloxacin, levofloxacin• T4: Levothyroxine• Piperadine antihistamine: Fexofenadine

Pharmacists’s Letter, www.pharmacistsletter.com 22

Drug-induced skin reactions• Extremely rare, yet potentially fatal skin reactions linked to acetaminophen

• Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Acute generalized exanthematous pustulosis (AGEP)

• Previously associated with • NSAIDs, e.g., ibuprofen, piroxicam, meloxicam • Sulfonamide antibiotics• Anticonvulsants, e.g., carbamazepine, phenytoin, lamotrigine, valproic acid, divalproex• Allopurinol

• Who is at risk? Risk factors unclear• Carbamazepine linked to some HLA-B variants found in 10% of population in parts of

Asia• Of those with the variant, 5% will have a serious dermatologic reaction to carbamazepine

• May occur at any time; more common early on – Recommendations for patients• STOP medication and contact prescriber at first signs of

• Skin pain, reddening, or blisters + systemic symptoms such as fever or sore throat.

• AVOID using the medication in future

• Acetaminophen and NSAIDs do NOT appear to cross-react• NSAIDs may be an alternative in patients with acetaminophen skin reactions.

US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com 23

http://www.fda.gov/


Olmesartan (Benicar) & GI effects• Olmesartan (Benicar) associated with enteropathy

• Severe chronic diarrhea, significant weight loss, and intestinal changes similar to celiac disease

• Uncommon, does not appear associated with other ARBs

• Onset months to years after starting olmesartan• Resolves when drug discontinued.

• Theorized mechanism• Delayed hypersensitivity reaction unique to olmesartan

• Recommendation: • Trial discontinuation olmesartan if no apparent cause for intestinal symptoms

• Note: • No clear evidence that olmesartan improves cardiovascular or renal

outcomes. • For most patients, ARB or ACEI proven to improve outcomes.

Facts & Comparisons eAnswers, www.factsandcomparisons.com; Pharmacist’s Letter, www.pharmacistsletter.com 24

http://www.factsandcomparisons.com/


QT prolongation & Torsades de Pointes• Growing list of associated meds

• Max doses lowered for: Citalopram, ondansetron• Indications limited for ketoconazole

• Risk factors for increased QT interval & Torsades de Pointes• Elder or female patients• Heart disease, slow heart rate• Liver or kidney disease • Low serum potassium or magnesium (Diuretic or laxative use may increased risk)

• Recommendation for higher risk patients: use alternatives, or monitor ECG

• Higher risk meds for (both) QT prolongation & torsades: • Quinidine, disopyramide, sotalol, clarithromycin, erythromycin, haloperidol, thioridazine,

chlorpromazine, and methadone

• Lower risk meds (less likely to torsades)• Amiodarone, azithromycin, quinolones (levofloxacin, etc), SSRIs, venlafaxine, ziprasidone• Note: May “tip balance” towards torsades if combined with riskier drugs in a high-risk

patient

• Drug interactions may increased blood levels of QT-prolonging meds• Strong 2D6 inhibotor (e.g., fluoxetine, paroxetine) + thioridazine

Pharmacist’s Letter, www.pharmacistsletter.com 25


Ketoconazole & CYP interactions• Ketoconazole (oral, systemic) use now limited to

systemic fungal infections • Serious hepatotoxicity• QT prolongation• Decreases cortisol secretion at doses > 400 mg/day• Dereases testosterone

• Impaired secretion at doses > 800 mg/day• Abolishes secretion ~ 1600 mg/day

• Drug interaction potential • Interactions QT prolongation

• Ketoconazole strongly inhibits CYP3A• Historically used in drug interactions studies

• Healthy individuals given 200 – 400 mg x 1, or daily for up to 5 days • Dose high enough to hepatotoxicity, adrenal

• Recommended alternatives: Clarithromycin, itraconazoleFacts & Comparisons, http://online.factsandcomparisons.com; US Food and Drug Administration, www.fda.gov 26

http://online.factsandcomparisons.com/

http://online.factsandcomparisons.com/

http://www.fda.gov/

Medications & Liver disease• Medications rarely increased liver function impairment

• Increased liver disease complications more likely, especially if cirrhosis advanced• Renal failure, GI hemorrhage, altered mental status

• Liver disease and renal failure often comorbid conditions• Reduce doses as appropriate based on renal function

• Acetaminophen Vs NSAIDs in liver disease• NSAIDs pose greater risk from renal failure or GI hemorrhage

• Use with caution, especially in cirrhosis

• Acetaminophen considered first choice for mild pain• Minimize dose, with max 2 – 3 grams/day

• Alternatives – tramadol or opioids in more severe pain• AVOID combining tramadol WITH opioids in cirrhosis – may hepatic encephalopathy

• Statin use in liver disease• Statin-associated hepatotoxicity very rare• In fatty liver or viral hepatitis, statins may improve liver function• Chronic stable liver disease, statin use considered acceptable• Acute liver failure, stop statins• Consider stopping statin if reducing cardiovascular risk no longer important



Drug shortages• Ongoing, growing concern since 2010

• Manufacturing slowdowns• Quality control concerns• Product discontinuation• Limited availability of raw materials

• Examples of currently affected drugs • Injectables, including nutritional, chemotherapeutic agents• Older antibiotics – e.g., tetracyclines• Levoxyl• Stimulants for ADHD, ADD

• For ongoing information about shortages• FDA Drug Shortage website http://

www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm• American Society of Health-System Pharmacists (ASHP) website http://

www.ashp.org/default.aspx

US Centers for Disease Control and Prevention, www.cdc.gov; US Food and Drug Administration, www.fda.gov 28

http://www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm



http://www.ashp.org/default.aspx



http://www.cdc.gov/

http://www.fda.gov/

New medications and Dosage forms

Pharmacist’s Letter; http://pharmacistsletter.therapeuticresearch.com 29

http://pharmacistsletter.therapeuticresearch.com/

http://pharmacistsletter.therapeuticresearch.com/

Summarizing new drugs & formulations

Neurology & mental health

• New drugs: 1• SSRI – Vortioxetine (Brintellix)

• New formulations: 8• Extended release formulations of desvenlafaxine, topiramate,

aripiprazole (injection)• SNRI – levomilnacipran• Transdermal sumatriptan• Also: clozapine oral suspension, SL buprenorphine/naloxone

Infectious diseases

• New drugs: 3• Botulism antitoxin, influenza vaccine (egg-free), integrase strand

transfer inhibitor for HIV-1 (dolutegravir)

• New formulations: 1• Tobramycin powder inhalation

30

Summarizing new drugs & formulationsWomen’s health

• New drugs: 2• Combination estrogen/SERM for osteoporosis prevention• Estrogen agonist/antagonist for dyspareunia

• New formulations: 7• 4 new contraceptives (chewable, lower estrogen, extended cycle,

intrauterine device)• Doxylamine/pyridoxine for pregnancy-related nausea and vomiting• Low-dose paroxetine for menopausal hot flashes• Oxybutnin patch (over the counter sales)

Diabetes

• New drugs: 4• Canagliflozin – Na-Glucose co-transporter 2 (SGLT2) inhibitor • Alogliptan – Gliptin (dipeptidyl peptidase-4, DPP-4) inhibitor

• Single agent and combination products 31

Summarizing new drugs & formulationsHyperlipidemia treatment• New drugs: 1

• Mipomerson – Oligonucleotide inhibitor of apolipoprotein B-100 synthesis (injectable)

Hematologic & bleeding management • New drugs: 2

• Prothrombin complex concentrate (PCC) – Reverses vitamin K antagonist (e.g., warfarin) effects

• Coagulation factor IX – bleeding control in hemophilia B

• New formulations: 1• Ferric carboxymaltose – iron replacement (infusion)

Respiratory agents• New drugs: 3

• 2 new agents for pulmonary hypertension • Endothelin receptor blocker & soluble guanylate cyclase stimulator

• Combined corticosteroid/long-acting beta agonist

• New formulations: 2• Ipratropium, ipratropium/albuterol inhalers reformulated

• CFCs, soy removed32

Summarizing new drugs & formulationsGastrointestinal agents• New formulations: 5

• Rabeprazole sprinkle caps• Esomeprazole strontium• 2 reformulations of UC meds

• Mesalamine, delayed release; budesonide extended release

• Osmotic laxative for bowel prep

Immunomodulatory agents• New drugs: 2

• Golimumab IV for RA• Dimethyl fumarate for MS (oral)

• New formulations: 1• Tacrolimus, extended relief

Antihistamines & combinations• New formulations: 2

• Carbinoxamine, extended release suspension• Hydrocodone/chlorphenirame

33

Summarizing new drugs & formulations

Antineoplastics• New drugs: 6

• Afatinib (Gilotrif)• Kinase inhibitor for metastatic non-small cell lung cancer

• Adotrastuzumab (Kadcyla) • HER2-targeted antibody & microtubule inhibitor for metastatic breast

cancer

• Trametinib (Mekinist), Dabrafenib (Tafinlar)• Kinase inhibitors for advanced melanoma with BRAF V600E and/or

V600K mutations

• Radium Ra223 dichloride (Xofigo)• Radioactive radium for advanced metastatic prostate cancer

• Pomalidomide (Pomalyst)• Thalidomide analogue for multiple melanoma

• Mechlorethamine (Valchlor) • Topical gel for cutaneous T-cell lymphoma

34

Summarizing new drugs & formulationsTopicals• New formulations: 4

• Brimonidine (Mirvaso) topical gel for rosacea• Desoximetasone (Topicort) spray for plaque psoriasis• Acyclovir (Sitavig) buccal tablet for recurrent oral HSV• Brinzolamide/brimonidine (Simbrinza) ophthalmic combination for glaucoma

Diagnostic agents• New drugs: 2

• Gadoterate meglumine – contrast agent for MRI• Technetium Tc 99m tilmanocept

• Radioactive imaging agent to help locate tumor-draining lymph nodes in breast cancer or melanoma

Miscellaneous agents• New drugs: 2

• Glycerol phenylbutyrate (Ravicti)• Help control blood ammonia levels in urea cycle (oral liquid)

• Cysteamine bitartrate (Procysbi), delayed release reformulation• For nephropathic cystinosis 35

New Generics in 2013• Zomig (zolmitriptan)

• Other triptans already available generically – sumatriptan, rizatriptan

• Niaspan (niacin extended-release)

• Lidoderm (lidocaine patch)

• Aciphex (rabeprazole) – due for release in November• Other generic PPIs – omeprazole, lansopraxole, pantoprazole• Nexium (esomeprazole) due for release in May 2014

• Lunesta (eszopiclone) – possible release in November• May be delayed due to legal hurdles• Other generic non-benzodiazepine hypnotic is zolpidem • Eszopiclone has shorter duration of action compared to zolpidem

• Cymbalta (duloxetine) – due for release in December 2013• Other generic SNRI – venlafaxine

• OxyContin (oxycodone ER) • Generics available in Canada• NOT equivalent to current (less-abusable) formulation of OxyContin



37

Diabetes

ADA Guidelines – Glucose, BP, & Lipid Control

Measure Treatment Goals

HbA1C < 7.0% (individualized)

Preprandial glucose 70-130 mg/dL (3.9-7.2 mmol/l)

Postprandial glucose < 180 mg/dL

Blood pressure < 130/80 mmHg (individualized)

Lipids

LDL: < 100 mg/dL (2.59 mmol/l)

< 70 mg/dL (1.81 mmol/l) (with overt CVD)

HDL: > 40 mg/dL (1.04 mmol/l)

> 50 mg/dL (1.30 mmol/l)

TG: < 150 mg/dL (1.69 mmol/l)

Adapted from: ADA. Diabetes Care 2012;35:S11–S63

HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides.

Diabetes• Goal: Normal, or near normal glycemia

• A1c goal < 7%• Test quarterly until stable• Test q 6 months in stabilized patients

• Note: A1c goal may differ based on individual risk factors• Higher goal if h/o severe hypoglycemia, limited life expectancy,

elder, some comorbidities

• Diet, exercise, weight loss central• Surgery an option if BMI > 35 • Medications for weight loss yield mixed results long-term

UpToDate, www.uptodate.com 39

http://www.uptodate.com/

Glycemic Control over time

After initial response,

• Each year, 5 – 10% fail to maintain target A1c

• After 3 years, 50% need a second drug

• After 9 years, 75% need multiple meds

Contributing factors

• Decreased adherence

• Weight gain

• Other illness

• Growing insulin resistance

• Increasingly deficient insulin production

• Type 1 destruction of pancreatic b-cell (LADA)

• Therapeutic inertia 40

Figure 1Diabetes Care 2012;35:1364–1379

Diabetologia 2012;55:1577–1596(Adapted with permission from: Ismail-Beigi et al. Ann Intern Med 2011;154:554)

Medications in diabetes type 2• First line: Metformin

• Consider insulin if BG, A1c very high or patient highly symptomatic

• Second line: 2nd oral or injectable agent • If not at goal A1c after 3 – 6 months• Insulin preferred if A1c >8.5% or hyperglycemia symptoms• ADA: Glucagonlike Peptide 1 (GLP-1) receptor agonist

• Exenatide (Byetta, Bydureon), Liraglutide (Victoza)

• Gliptins (sitagliptin, etc)• (Possibly) pioglitazone• Short-acting sulfonylurea (glipizide, glimipiride)

ADA Standards of Medical Care in Diabetes 2013, http://professional.diabetes.org; UpToDate, www.uptodate.com 42

http://professional.diabetes.org/



T2DM Anti-hyperglycemic Therapy: General Recommendations

Diabetes Care 2012;35:1364–1379Diabetologia 2012;55:1577–1596

Long-acting exenatide (Bydureon)• Glucagon-like peptide 1 (GLP-1) agonist

• Injected once a week • Others injected daily - Once daily (liraglutide, Victoza), or twice daily (exenatide, Byetta)

• Add-on therapies to improve glycemic control and help with weight loss

• Efficacy: • A1c decrease similar for Bydureon, Victoza (liraglutide); regular exenatide

(Byetta) less effective• Weight loss similar for all GLP-1 agonists (~6 – 8 lbs in 6 months)

• Adverse effects: • Nausea – Usually improves within a few weeks• Lump at injection site – Usually fades as medication absorbed• Pancreatitis: Rare• Exenatide products associated with dose- and treatment duration-related

thyroid C-cell tumors (in rodents)

• Note: Bydureon unavailable in a pre-mixed pen (ER formulation)




Glucagon-like peptide 1 (GLP-1) agonists(incretin mimetics) in Summary

• Note: Dosing varies depending on patient population, concomitant disease states, and/or drug therapy.

• aIn 1.2 and 2.4 mL prefilled pens

• bIn 3 mL prefilled pensAdapted from: Facts & Comparisons eAnswers, www.factsandcomparisons.com

45

Generic name Exenatide Exenatide ER Liraglutide

Trade name Byetta Bydureon Victoza

Dosage forms Injection, solution: Injection, powder Injection, solution:

strengths available 250 mcg/mLa for suspension, 6 mg/mLb

ER: 2 mg

Initial adult dose 5 mcg 2 mg 0.6 mg

subcutaneously subcutaneously subcutaneously

twice daily once weekly once daily

Maintenance 10 mcg 2 mg 1.2 to 1.8 mg

adult dose subcutaneously subcutaneously subcutaneously

twice daily once weekly once daily


Gliptins or DPP-4 Inhibitors (incretin mimetics)

• Use: Type 2 diabetes• Nearly 25% of DM patients take a gliptin

• New drug alogliptin (Nesina)• Similar to sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta)• Available in combination with other type 2 DM meds

• Alogliptin + metformin (Kazano)• Alogliptin + pioglitazone (Oseni)

• Usual dosing: 25 mg po q day (CrCl > 60 ml/min)• 12.5 mg po q day (CrCl = 30 – 60 ml/min)• 6.25 mg po q day (CrCl < 30 ml/min)

• Add-on therapy for patients close to their A1C goal, with high postprandial glucose• After lifestyle changes, metformin

• Benefits include low risk for:• Hypoglycemia• Weight gain

• Modest efficacy: Lower A1c 0.7 - 1% after 6 months of therapy• Sulfonylureas, GLP-1 agonists (Byetta, Victoza, etc), pioglitazone lower A1C ~ 1 – 1.5%

US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com 46

http://www.fda.gov/


Gliptins (DPP-4 Inhibitors), cont• Adverse effects

• Nasopharyingitis, headache, upper respiratory tract infection• Possible increased risk for acute pancreatitis (small, unclear) • Gliptins and risk for cardiovascular events

• Ischemic events: Neither increase nor decrease with saxagliptin (Onglyza), alogliptin (Nesina) • Saxagliptin MAY increase hospitalizations for heart failure.

• Not enough information to indicate if possible gliptin class effect• Appears to be less likely to do this than the thiazolidinedione pioglitazone (Actos)

• Concerns:• Costly (~$8/day) • Possible increased cardiovascular risk • Possible pancreatitis risk

• Consider gliptins for patients • Close to goal A1c • Impaired renal function AND unable to take metformin or a sulfonylurea

• Choosing a gliptin• If CYP 3A4 interactions a concern, consider alogliptin (Nesina) or sitagliptin (Januvia)• If renal impairment, no dose adjustment needed for linagliptin (Tradjenta)

• Lower doses recommended with other gliptins

• Use saxagliptin with caution in heart failure



Incretin mimetics & pancreatitis risk• Incretin mimetics (gliptins and GLP-1 agonists) may increased

acute pancreatitis risk• ~ 1 case acute pancreatitis per 50 patients after up to 2 years of use • Theorized mechanism:

• Incretin mimetics may inflammation, acute pancreatitis and possibly pancreatic cancer

• Acute pancreatitis risk factors• Diabetes• Alcohol or tobacco use• Gallstones• High triglycerides• Obesity

• Recommendation for patients using incretin mimetics: • Report severe abdominal pain and vomiting immediately • Emphasize importance of controlling other risk factors



Canagliflozin (Invokana)• Inhibits Sodium-glucose co-transporter 2 (SGLT2) in kidneys

• Increases glucose loss through urine• Other SLGT2 inhibitors in development pipeline – dapagliflozin (Forxiga), ipragliflozin,

empagliflozin

• Efficacy: Reduces A1c ~ 1% when used alone• Benefits:

• Low risk for hypoglycemia• Lowers blood pressure • Helps with weight loss (modest)

• Suggested place in therapy• Add-on to metformin after failure with other 2nd line agents – e.g., sulfonylureas, gliptins,

pioglitazone

• Dosing• Starting dose = 100 mg po q day, taken within 30 minutes of first meal of day• Increase dose to 300 mg po q day if none to mild moderate renal impairment

• Adverse effects: • Urinary tract infections• Diuretic effect may increased urination and risk for dehydration• May increase LDL by 4% to 8%• Cardiovascular safety unknown

• Monitoring• Hyperkalemia in patients at risk

• Mild renal impairment, concomitant use of ACEIs, ARBs, potassium-sparing diuretics, etc. Pharmacist’s Letter, www.pharmacistsletter.com 49


• ASK about hypoglycemia (symptoms) at every visit• Hypoglycemia may confusion, seizures, ER visits, etc

• Prevention starts with A1c goal tailoring• Usual A1c goal < 7% • Consider up to 8% if at risk for severe hypoglycemia, multiple comorbidities

• Reducing hypoglycemia risk due to meds• Insulin patients

• Rapid-acting insulin (e.g., Humalog) instead of insulin R• Long-acting basal insulin (e.g., Lantus, Levemir) instead of insulin

• Add-ons to metformin – Gliptin (e.g. Januvia), GLP-1 agonist (e.g., Byetta, Victoza), pioglitazone• About sulfonylureas:

• Short-acting sulfonylureas - glipizide or glimepiride pose less risk for hypoglycemia, accumulation in renal impairment

• Avoid combining with insulin – adds little benefit, may increase hypoglycemia risk

• Treating hypoglycemia: "test, treat, test, eat" • TEST blood glucose if symptoms - Shaking, sweating, palpitations, dizziness, etc. • TREAT if glucose < 70 mg/dL, or below 80 – 90 mg/dL (elder patients)

• Suggestions: 15 – 20 g simple carbs – 3 – 4 glucose tabs, 5 – 6 hard candies, etc

• Re-TESTing after 15 minutes, then repeat treatment if needed• EAT a small meal when glucose is back in range

• Consider glucagon if patient at risk for severe hypoglycemia• Be sure patient’s family, friends know how to use it.

ADA Standards of Medical Care in Diabetes 2013, http://professional.diabetes.org;; Pharmaicst’s Letter, www.pharmacistsletter.com 50

Diabetes – Preventing hypoglycemia



Managing diabetes during cough & cold season• Acute illness may stress HYPERglycemia

• However, less intake due to anorexia, nausea, or vomiting may HYPOglycemia

• Individualize therapy based on condition and testing – test more frequently• If type 2 DM and NOT on insulin, test 2 – 4 times a day• If using insulin, test up to q 2 – 4 hours • If type 1 DM, consider ketone testing if glucoses persistently > 250 mg/dL

• Ketone testing not usually needed in type 2 DM (diabetic ketoacidosis less common)

• Oral meds and non-insulin injectable meds• Do not automatically stop, even if not eating• Exception: Metformin – if patient becomes dehydrated, lactic acidosis is a risk• Metformin: Hold if vomiting or severe diarrhea

• Restart when eating and drinking resumed

• If hypoglycemia risk, consider holding sulfonylureas, repaglinide, or nateglinide

• Insulin• Do NOT stop insulin during acute illness - Sometimes HIGHER doses needed• If glucose > 250 mg/dL, increase rapid-acting insulin dose, generally by 5 – 20% of total daily

dose• If unable to adequate carbs, consider lowering or skipping BOLUS doses (Humalog) • Continue BASAL insulin (Lantus) - Consider dose reduction if patient unable to eat

• When to call provider or seek urgent care: • Glucose > 300 mg/dL x 2 over several hours• Some patients may need insulin on a short-term basis• Emergency care recommended if prolonged vomiting, can't hydrate, or persistent hyper- or

hypoglycemiaPharmacist’s Letter, www.pharmacistsletter.com 51


Diabetes – V-Go device• Insulin delivery system worn like a patch, attached to abdomen or arm daily

• Alternative to insulin pump for continuous delivery, with rapid-acting insulin infused SC over 24 hours

• Mealtime bolus option, 2 units at a time

• Available in 3 sizes, delivering 20, 30, or 40 units/24 hrs• Plus boluses up to 36 units/day

• Cost is ~ $215/month in addition to insulin cost

• Somewhat cumbersome to use• Requires multiple steps to fill with insulin, must be replaced daily

• Not appropriate for patients who• Fine-tune insulin doses• Require > 76 units/day.



Hypertension, Hyperlipidemias,

and Cardiovascular

Disease

53

Hypertension & hyperlipidemias in overviewBlood pressure goals

• Usual: BP < 140/90 mmHg • Elders with diastolic BP < 60 mmHg, set systolic goal < 150 mmHg• Diabetes: No evidence for benefits when systolic < 130 mmHg

Uncomplicated hypertension – start with any of the following

• Thiazide diuretic (both show better outcomes than HCTZ)• Chlorthalidone 12.5 – 25 mg po q day• Indapamide 1.25 – 2.5 mg po q day

• ACE inhibitor or Angiotensin receptor blocker (ARB)

• Calcium channel blocker (CCB)

BP management post-MI or heart failure

• Beta-blockers

Hyperlipidemias

• Set individual LDL goals based on percentage reductions• Ex. If goal to lower LDL by 30% to 40%, consider atorvastatin 10 mg/day, simvastatin

20 – 40 mg/day, rosuvastatin 5 mg/day

• Statins emphasized over add-on therapies (e.g., niacin, fibrates, ezetimibe) • Statins improve CV outcomes, little evidence for same with add-on therapiesPharmacist’s Letter, www.pharmacistsletter.com 54


Blood pressure goals in diabetes• Systolic BP < 140 mmHg

• Goal < 130 mmHg if possible without “undue treatment burden”

• Younger patients• Patients with high risk for, or history of stroke• Renal disease with significant proteinuria

• Increased adverse effects associated with BP <120 mmHg• RCT showed increased hypotension, hyperkalemia without benefit

• In stroke, intensive BP lowering prevents 1 stroke for 89 patients treated x 5 years

• Lower systolic BP may slow kidney disease progression

• Diastolic BP < 80 mmHg

ADA Standards of Medical Care in Diabetes, 2013; Pharmacist’s Letter, www.pharmacistsletter.com 55


Improving outcomes post-MI• ACE inhibitors

• Lisinopril 20 mg po q day• Ramipril 10 mg po q day• Trandolapril 4 mg po q day

• ARBs (if ACEIs not tolerated)• Candesartan 32 mg po q day• Telmisartan 80 mg po q day • Valsartan 320 mg po q day.

• Beta-blockers (titrate dose over a few weeks to months to resting pulse 55 – 60 bpm)• Metoprolol 200 mg/day• Carvedilol 50 mg/day

• Statins (treatment goal: reduce LDL by 50 – 60%)• Atorvastatin 80 mg po q day has been shown to reduces risk of CV events & mortality post-MI

•

• Titrate to target doses • Note: < 1/3 patients get the "target doses" of ACEI or ARB, beta-blocker, & statin

• Not everyone achieves target doses , due to side effects, renal or hepatic impairment, or interactions.

• Monitoring parameters for ACEIs, ARBs: BP, serum potassium, renal function• Monitoring parameters for beta-blockers: BP, HR• If hypotension, reduce doses of other CV meds first – e.g., diuretics, nitrates, & calcium channel

blockers.• Monitoring parameter for statins: LDL, other lipids

UpToDate, www.uptodate.com; Pharmacist’s Letter, www.pharmacistsletter.com 56



Antihypertensive meds & Alzheimer’s risk

• Secondary analysis of the Ginkgo Evaluation of Memory Study in older adults

• Age > 75 years with normal cognition or mild cognitive impairment (MCI)

• Median 6.1 year follow-up

• Evaluate risk of developing Alzheimer’s disease (AD) based on antihypertensive use

• Diuretics (15.6% participants)

• Angiotensin-1 receptor blockers (ARB) (6.1% participants)

• Angiotensin-converting enzyme inhibitors (ACE-I) (15.1% participants)

• Calcium channel blockers (CCB) (14.8% participants)

• B-blockers (BB) (20.5% participants)

• 2,248 participants taking antihypertensive meds; 290 (13%) developed AD

• Conclusions:

Normal cognition participants:

• Diuretic, ARB, & ACE-I use associated with reduced risk of AD dementia

• In addition to and/or independently of mean systolic blood pressure

Mild cognitive impairment

• Diuretic use (only) associated with reduced risk

Yasar, Neurology 2013; 81: 896 - 903 57

Using beta blockers• Uncomplicated hypertension: 4th line therapy

• Consider after diuretic, ACEI or ARB, and calcium channel blocker

• Concern:• Beta-blockers show less benefit in preventing CV events compared to other BP

meds• Despite lowering BP to a similar level

• Atenolol used most in these trials – unknown if lack of benefit unique to atenolol• Possible class effect currently under evaluation

• Theory: Atenolol approved for once-daily dosing, yet effects may not last all day.

• Suggested action: If beta-blocker indicated for hypertension, use a different agent, or dose atenolol BID

• Beta blockers still recommended in heart failure, post-MI (min 2 – 3 years)

• Some beta-blockers shown to improve CV outcomes• Heart failure - carvedilol, extended-release metoprolol, or bisoprolol. • Post-MI - metoprolol or carvedilol recommended




Edarbyclor (Chlorthalidone + azilsartan)• First combination containing chlorthalidone in 20 years

• Other chlorthalidone combinations contain atenolol or clonidine

• Advantages over using HCTZ• Longer acting • Better efficacy in lowering BP • More evidence for improved cardiovascular outcomes, survival

• Hypokalemia concern lower than with past use• Lower dose of chlorthalidone• Combination with ARB (same holds if combining with ACEI)

• Dosing: 12.5 – 25 mg daily of chlorthalidone• If switching from HCTZ, start with half current HCTZ dose • Note: If prescribing chlorthalidone alone, patient will need pill cutter for 12.5 mg

dose (25 mg tabs not scored)

• Endarbyclor strengths: • 40 mg azilsartan + 12.5 mg chlorthalidone• 40 mg azilsartan + 25 mg chlorthalidone




Heart Failure – New guidelines• Goals

• Improve quality of life• Reduce progression to more advanced stages• Reduce risk of fatal cardiac events

• Guideline-directed medical therapy (GDMT) • Term applied to optimal treatment recommendations based on highest level of

evidence for effectiveness• Includes lifestyle modification• Control of diastolic and systolic hypertension

• Optimal BP management reduces HR risk by half

• Address• Initial and continuing evaluation of heart failure• Treatment of patients in different stages• Management of acute heart failure in hospitalized patients

• Separate recommendations for patients with • Preserved left ventricular ejection fraction• Reduced ejection fraction

American College of Cardiology (ACC) Foundation and American Heart Association (AHA) Guidelines for Heart Failure Management 60

Heart Failure - GDMTStructural heart disease without heart failure symptoms

ACC–AHA heart failure stage B

• Routine use: ACEI or ARB + β-locker

• Add statin if history includes myocardial infarction (MI) or acute coronary syndrome

Stage C + fluid overload

• Add loop diuretic

• If persistently symptomatic African American, recommendation is hydralazine nitrates

Stage C with NYHA functional class II, III, or IV heart failure + ejection fraction < 35%

Acute MI and ejection fraction < 40% + heart failure symptoms or history of DM

• Include aldosterone antagonist (both groups)

• Update in new guidelines - previously aldosterone antagoinists only recommended in severe heart failure

• Evidence shows reduced mortality and hospitalizations in patients with less severe disease

• Monitor renal function when using aldosterone antagonistAmerican College of Cardiology (ACC) Foundation and American Heart Association (AHA) Guidelines for Heart Failure Management 61

Heart Failure – GDMT in the hospital Reduced ejection fraction, hospitalized with acute exacerbations

• Continue, intensify oral maintenance therapy

• IV loop diuretics• Evidence of "significant" fluid overload• If patient previously on oral loop diuretic, IV dose > oral dose• Administer as continuous infusion or intermittent boluses• Monitor fluid output and congestion status, then adjust dose accordingly

• Withhold or reduce β-blocker therapy ONLY if • Recent dose increase OR• Recently initiated

• Initiate β-blocker therapy after • Stabilizing patient• Volume status optimization

• IV diuretics, vasodilators, and inotropic agents are discontinued.

• Start with low dose β-blocker therapy

American College of Cardiology (ACC) Foundation and American Heart Association (AHA) Guidelines for Heart Failure Management 62

Heart Failure Guidelines, cont• Monitoring: Blood pressure + Fluid status

• Encourage daily weight monitoring at home• Biomarkers to consider in clinically euvolemic outpatients

• Brain natriuretic peptide (BNP)• N-terminal pro-B-type natriuretic peptide (NT-proBNP)• BNP-directed therapy most appropriate in chronic heart failure

• Usefulness not established in acute decompensated heart failure (hospitalized patients), hospitalization reduction, outpatient death reduction

• Patient support & education• Help patient understand about medications

• Particularly important at time of hospital discharge• Heart failure patients at high risk for readmission within 30 days

• Encourage participation in outpatient disease management program

• Multidisciplinary team approach recommendedAmerican College of Cardiology (ACC) Foundation and American Heart Association (AHA) Guidelines for Heart Failure Management 63

Guidelines (2004) for initiating therapeutic changes to achieve goal LDL

National Cholesterol Education Program (NCEP) Guidelines, 2004 64

Cardiovascular Risk LDL-C Goal Initiate Lifestyle Changes

Consider Drug Therapy

High Risk (existing CHD or CHD equivalents; 10-year risk > 20%)

< 100 mg/dL (optimal goal: < 70 mg/dL)

> 100 mg/dL > 100 mg/dL

Moderately High Risk (2+ risk factors; 10-year risk 10% to 20%)

< 130 mg/dL > 130 mg/dL > 130 mg/dL

Moderate Risk (2+ risk factors; 10-year risk < 10%)

< 130 mg/dL > 130 mg/dL > 160 mg/dL

Lower Risk (0-1 risk factors)

< 160 mg/dL > 160 mg/dL > 190 mg/dL

Do statins increase risk of injury during exercise? Do statins limit the benefits of exercise?• Evidence conflicts

• Some show no reduction in strength or exercise performance

• Exercise recommended for all patients, including those on statins• Improved survival with exercise + statin compared to either alone• Start slow, increase as tolerated to 30 minutes of moderate intensity activity most days if possible. • For statin patients, increase duration before increasing intensity• Cross training helps avoid overuse

• Distinguishing between statin-related and exercise-related muscle pain• Ask about recent changes in activity or meds• Statin muscle symptoms usually symmetric, widespread, often in larger muscles, e.g., calves,

thighs

• Consider checking creatine kinase levels• Rise with exercise alone• If very elevated, discontinue statin

• Strategies to minimize statin muscle pain• Co-enzyme Q10 supplementation may help, no solid evidence of benefit• Lowering the dose or dose every other day• Change statins (simvastatin more associated with myopathy)• Avoid interacting meds




Triglycerides & Fish Oil (Vascepa, Lovasa)• Vascepa (vas-EE-puh, icosapent ethyl)

• New EPA only fish oil product for lowering triglycerides• Less likely to increase LDL like EPA/DHA combos

• Comparing Rx fish oil products (Vascepa, Lovasa)• Both contain 1 gram omega-3 FAs per capsule• Vascepa 4 g/day lowers TGs ~ 27% form baseline

• Note: May be less effective for lowering triglycerides (TGs)

• Lovaza 4 g/day lowers TGs ~ 45%, AND may increase LDL ~ 45%• Both can be costly ~ $185/month

• Conventional recommendations in high triglycerides• Focus on lifestyle changes – weight loss, exercise, glucose management, limiting

alcohol intake, etc• Triglycerides < 500 mg/dL

• Statin recommended – statins may reduce triglycerides up to 30%

• Triglycerides > 500 mg/dL• Consider adding fish oil, fibrates, or niacin• No evidence for improved CV outcomes with using these for lowering triglycerides

• Note: Lowering triglycerides does NOT decrease pancreatitis risk unless baseline triglycerides > 1000 mg/dL

Natural Medicines Comprehensive Database, www.naturaldatabase.com; Pharmacist’s Letter, www.pharmacistsletter.com 66

http://www.naturaldatabase.com/


Lipids and probiotics

• Cardioviva – probiotic marketed to help lower cholesterol• Contains Lactobacillus reuteri• Lowers LDL ~ 8 – 11% • Similar to reductions associated with cholestyramine, psyllium,

phytosterols

• Theorized mechanism• May reduce absorption or dietary fat, cholesterol• May reduce bile salt entero-hepatic recycling

• Notes: • Other probiotic species shown to help reduce serum lipids• No evidence that probiotic use leads to improved CV outcomes• Best as adjunct to, rather than replacement for

• Diet and lifestyle changes• Statins

Natural Medicines Comprehensive Database, www.naturaldatabase.com; Pharmacist’s Letter, www.pharmacistsletter.com 67

http://www.naturaldatabase.com/


Chronic Obstructive Pulmonary Disease

68

Managing COPD• Goals: Control symptoms, decrease exacerbations, improve

patient function and quality of life• Disease severity guides therapeutic choices

• Mild symptoms: short-acting anticholinergic + beta-agonist prn• E.g., Ipratropium + albuterol, alone or combined

• Moderate to severe or persistent symptoms: • Long-acting anticholinergic (e.g., tiotropium, aclidinium), AND/OR • Long-acting beta-agonist (salmeterol, etc)

• Severe symptoms, frequent exacerbations, or asthma symptoms• Add inhaled steroid • Note: increase risk of pneumonia, possibly fractures• Combined long-acting beta-agonist + steroid products

• Breo Ellipta (fluticasone furoate + vilanterol) – Q day dosing• Advair (fluticasone + salmeterol) – BID dosing• Symbicort (budesonide + formoterol) – BID dosingUpToDate, www.uptodate.com; Pharmacist’s Letter, www.pharmacistsletter.com 69



Managing COPD• Acute exacerbations

• Recommendation: Prednisone 40 mg po q day x 5 days• Guidelines still recommend 10 to 14 days of oral steroids, yet shorter

5-day courses usually sufficient

• Higher doses more adverse effects • No increase in efficacy with IV use

• What about beta-blocker use? • Traditionally avoided due to possible bronchospasm worse

COPD symptoms• Now considered acceptable if indicated (e.g., for heart disease)• Growing evidence for decreased exacerbations, improved survival

• Recommendations: • Cardioselective b-blockers (e.g., metoprolol, bisoprolol)• Avoid non-selective b-blockers (e.g., carvedilol) • Start with low dose, then monitor pulmonary function

UpToDate, www.uptodate.com; Pharmacist’s Letter, www.pharmacistsletter.com 70



Infectious Diseases

71

Doxycycline shortage• Background

• Broad-spectrum bacteriostatic antibiotic used for many conditions• Treatment of choice for rickettsial infections• No data supporting efficacy for minocycline as alternative• Minocycline adverse effects higher with minocycline• Tetracycline may be alternative, however, shortages also reported

CDC Recommendations

• Doxycycline remains treatment of choice • Suspected rickettsial infections

• No alternatives have same proven efficacy limiting fatal outcome

• Lyme disease prophylaxis• Alternatives not tested for efficacy• Providers apply clinical judgment following a tick bite.

• Malaria treatment and prophylaxis • Doxycycline drug of choice• Lyme disease treatment• Providers urged to use clinical judgment in treatment choices

• Where alternatives exist, providers recommended to apply clinical judgment • Sexually transmitted infection treatment• Lyme disease treatmentCDC Health Alert Network, CDCHAN-00349, http://emergency.cdc.gov/HAN/han00349.asp 72

http://emergency.cdc.gov/HAN/han00349.asp


Doxycycline & Tetracycline shortagesNote: Doxycycline hyclate and monohydrate salts equally effective (hyclate salt may more GI upset)

Alternatives by indication

• Community-acquired methicillin-resistant staph aureus (MRSA) skin infections• Consider: TMP/SMX, clindamycin, or minocycline• (Last resort) Linezolid (Zyvox)

• Acne and rosaceaMilder cases: Consider topical agents

Moderate to severe cases• Acne: Consider erythromycin or (possibly) minocycline • Rosacea: Consider metronidazole or Oracea (doxycycline) for rosacea.

• H. pylori – Quadruple therapy generally most effective: PPI, bismuth, tetracycline, metronidazole• Consider PPI + Pylera or Helidac

• Combo packs contain tetracycline, bismuth, and metronidazole

• Consider triple therapy + metronidazole to help boost efficacy: PPI, clarithromycin, amoxicillin, metronidazole

• Community-acquired pneumonia• Consider clarithromycin or azithromycin• If bacterial resistance likely, ADD high-dose amoxicillin or switch to levofloxacin or moxifloxacin

• Especially applicable in patients with comorbidities such as heart, lung, or kidney disease, diabetes, immunosuppression

• Early Lyme disease• Consider amoxicillin or cefuroxime

Facts & Comparisons, www.factsandcomparisons.com; Pharmacist’s Letter, www.pharmacistsletter.com 73



Macrolides and URIs• NOT recommended for most acute respiratory infections

• Pneumococcal resistance rising • Many penicillin resistant strains also resistant to macrolides

• Avoid macrolides for acute otitis media or sinusitis

• Reserve macrolides for special circumstances

• Strep throat• First line: Beta-lactam (e.g., penicillin, amoxicillin)

• Reserve azithromycin only for patients who have a life-threatening allergy to

beta-lactams

• Community-acquired pneumonia• Azithromycin or clarithromycin only when atypical bacteria (e.g.,

Mycoplasma) suspected • Based on presentation – e.g., prominent cough, slower onset, milder symptoms, etc.



Beta-lactam allergy• Patients often confuse allergies and adverse effects

• Up to 90% of patients who report penicillin allergy • Test negative on skin test, AND • Tolerate penicillin on trial dosing

• Low allergic cross re-activity between penicillin & cephalosporin• Positive skin test to penicillin: ~ 2% of patients also react to a

cephalosporin• Only 0.1% among patients with history of mild penicillin reaction

• In general, people allergic to penicillin are 3 X more likely to react to unrelated drug

• First generation cephalosporins more likely to cross-react

• Penicillins & cephalosporins with the same R-group side chains • Amoxicillin, cefadroxil, cefprozil• Ampicillin, cefaclor, cephalexin



Alternatives in beta-lactam allergyRecommendations • NON-severe penicillin allergy

• e.g., minor, non-pruritic rash, especially if > 10 years ago• Best to avoid cefprozil or cefadroxil due to shared side chain• Trial of other cephalosporin acceptable• Consider graded challenge:

• Give 10% of dose, wait 1 hour, then give rest of dose if no reaction

• Severe penicillin allergy• Allergy testing recommended before cephalosporin use for patient with

history of hives, angioedema, or anaphylaxis

• Alternatives differ by indication• Respiratory quinolone (levofloxacin, etc)

• Note not as risky in children as previously thought

• Doxycycline• Clindamycin• Macrolides

• Note: rising resistancePharmacist’s Letter, www.pharmacistsletter.com

76


Drug Resistance Threats• Recent CDC report recommends

• Infection prevention whenever possible through hand and personal hygiene, etc.

• Antimicrobial resistance present in every community, every health care facility, every medical practice

• Up to 50% human antimicrobial use unnecessary, may contribute to rising resistance

• Resistance poses dire threat to public health – Annually,• 2 million Americans develop illness from drug-resistant organisms• At least 23,000 people die

• Antimicrobial stewardship programs to ensure safe and appropriate use

• Recommended phase-out of nontherapeutic use in animals• Primary area of concern: hospital use

CDC 2013 Threat Report, http://www.cdc.gov/drugresistance/threat-report-2013/ 77

http://www.cdc.gov/drugresistance/threat-report-2013/

CDC Report on drug resistance threat• 4 areas highlighted for appropriate action to reduce threats

• 18 organisms pose greatest public health threat• 3 organisms pose urgent threat• 12 organisms pose serious threat• 3 organisms pose concerning threat

• Organisms that pose urgent threat• Clostridium difficile

• Although C. difficile strains not yet seriously drug resistant, infections are directly linked to antimicrobial use and misuse and affect thousands of Americans each year.

• Estimated at least 250,000 C. difficile infections annually in US, with at least 14,000 deaths

• Carbapenem-resistant Enterobacteriaceae (CRE)• Rank high on the threat list because they freely exchange resistance genes with other

organisms• Estimated 10,000 infections, with 600 deaths annually

• Drug-resistant Neisseria gonorrhea.• Estimated ~ 800,000 cases of gonorrhea annually in US• Two first-line treatments• Resistance to ceftriaxone would cripple national efforts to control gonorrhea

CDC 2013 Threat Report, http://www.cdc.gov/drugresistance/threat-report-2013/ 78



Influenza Vaccine• Four versions for 2013 – 2014: Trivalent, quadrivalent, cell culture, & recombinant

• Quadrivalent vaccines

• Protect against 4 flu virus strains instead of the usual 3 • Children, teens most affected by the two B strains covered by the quadrivalent

• FluMist is available as quadrivalent ONLY • Noninjectable option for healthy, nonpregnant patients ages 2 – 49 yeas

• Fluarix, FluLaval, and Fluzone • Available as BOTH quadrivalent and trivalent

• All other flu vaccines trivalent

• ~ 20% of this year’s will be quadrivalent

• Flucelvax cell culture vaccine – original viruses grown in eggs• Trivalent• Approved for adults only• NOT guaranteed egg-free – may contain TRACE amounts of egg protein

• Flublok recombinant vaccine – viral proteins that trigger immunity replicated ONLY

• Trivalent• Approved for ages 18 – 49• Completely egg-free and suitable for those with severe egg allergy

Pharmacist’s Letter. www.pharmacistsletter.com 79


END

Questions?

80

Thanks!Contact information

Petra Eichelsdoerfer, ND, CN, [email protected]

81

mailto:[email protected]

Helpful resources: Free & Government

• Daily med (http://dailymed.nlm.nih.gov)• Package inserts for many prescription medications

• Food and Drug Administration (FDA) (www.fda.gov)

• Centers for Disease Control and Prevention (CDCP) (www.cdc.gov)

• Linus Pauling Institute at Oregon State University (http://lpi.oregonstate.edu/infocenter/)

• MedScape (www.medscape.com) – general clinical focus, continuing education, and helpful case studies

82

http://dailymed.nlm.nih.gov/

http://www.fda.gov/

http://www.cdc.gov/

http://lpi.oregonstate.edu/infocenter/

http://lpi.oregonstate.edu/infocenter/

http://www.medscape.com/

Helpful resources: Subscription • Pharmacist’s Letter/Prescriber’s Letter (

www.pharmacistsletter.com or www.prescribersletter.com)

• Lexicomp (www.lexi.com) printed and electronic clinical tools

• The Drug Information Handbook (annually updated) • Drug interactions checker

• Facts and Comparisons (www.factsandcomparisons.com) printed and electronic references

• Facts and Comparisons E Answers (with pill ID and interactions checker)

• ClinicalKey (https://www.clinicalkey.com) – clinically focused information; full-text references, full access articles, patient handouts

83


http://www.prescribersletter.com/

http://www.lexi.com/


https://www.clinicalkey.com/

https://www.clinicalkey.com/

For more information on alternatives to doxycycline

Rickettsial infections• Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain

Spotted Fever, Ehrlichiosis and Anaplasmosis – United States (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm).

Lyme Disease• 2006 guidelines for treatment developed by the Infectious Diseases Society of

America (IDSA) (http://cid.oxfordjournals.org/content/43/9/1089.full). • For more information on prophylaxis of Lyme disease, see the 2006 IDSA

guidelines (http://cid.oxfordjournals.org/content/43/9/1089.full).

Malaria• CDC malaria website (http://www.cdc.gov/malaria)

Sexually Transmitted Diseases• For alternative regimens using other antibiotics, see the 2010 STD Treatment

Guidelines (http://www.cdc.gov/std/treatment/2010/default.htm). • For additional recommendations, contact a specialist or local health department

CDC Health Alert Network, CDCHAN-00349, http://emergency.cdc.gov/HAN/han00349.asp 84

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm

http://cid.oxfordjournals.org/content/43/9/1089.full

http://cid.oxfordjournals.org/content/43/9/1089.full

http://www.cdc.gov/malaria

http://www.cdc.gov/std/treatment/2010/default.htm



New Drugs & Dosage Forms:

Summary Tables

85

Neurology & Mental Health

Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com 86

Brand Generic Description

New Drug

Brintellix vortioxetine An SSRI for treatment of depression.

New Formulations

Abilify Maintena aripiprazole Extended-release injectable formulation for schizophrenia.

Fetzima levomilnacipran An SNRI for depression. The levo isomer of milnacipran (Savella).

Khedezla desvenlafaxine A new extended-release tablet formulation for depression.

Nymalize nimodipine New oral solution to improve neurological outcomes post subarachnoid hemorrhage.

Trokendi XR topiramate New extended-release capsule formulation for seizures.

Versacloz clozapine New oral suspension formulation for schizophrenia.

Zecuity sumatriptan New iontophoretic transdermal system for acute treatment of migraine.

Zubsolv buprenorphine/ naloxone

New sublingual tablet formulation for maintenance treatment of opioid dependence.

http://www.fda.gov/


New Drugs & Formulations – Infectious DiseaseBrand Generic Description

New Drugs

BATbotulism antitoxin heptavalent (equine)

Immune globulin fragments for treatment of symptomatic botulism.

Flublok influenza vaccine

A cell culture vaccine for prevention of influenza in people 18 through 49 years of age. Neither influenza virus nor eggs are used in its production.

Tivicay dolutegravirAn integrase strand transfer inhibitor for HIV-1 infection.

New Formulation

TOBI Podhaler

tobramycinNew oral inhalation powder formulation for cystic fibrosis patients with Pseudomonas aeruginosa


http://www.fda.gov/


New Drugs – Women’s Health



Duaveeconjugated estrogen/bazedoxifene

Combination estrogen/SERM for menopausal vasomotor symptoms and prevention of postmenopausal osteoporosis.

Osphena ospemifeneAn oral estrogen agonist/antagonist for painful sexual intercourse due to menopause.

http://www.fda.gov/


New Formulations – Women’s Health



Lo Minastrin FE ethinyl estradiol/ norethindrone/ ferrous fumarate

New low-dose (10 mcg estrogen) oral contraceptive tablets.

Minastrin 24 FE ethinyl estradiol/ norethindrone/ferrous fumarate

New chewable tablet formulation oral contraceptive.

Quartette levonorgestrel/ethinyl estradiolNew 84-day extended-cycle oral contraceptive with gradually increasing doses of estrogen.

Skyla levonorgestrelNew progestin-containing intrauterine system for prevention of pregnancy for up to three years.

Diclegis doxylamine/pyridoxineA combination antihistamine/vitamin B6 for pregnancy-related nausea and vomiting.

Oxytrol for Women oxybutyninNew over-the-counter version of the oxybutynin patch for women with overactive bladder.

Brisdelle paroxetine New low-dose (7.5 mg) capsule for menopausal hot flashes.

http://www.fda.gov/


New Drugs - DiabetesBrand Generic Description

Invokana canagliflozinA sodium-glucose co-transporter 2 (SGLT2) inhibitor to increase glucose excretion in patients with type 2 diabetes.

Nesina alogliptinNew dipeptidyl peptidase-4 (DPP-4) inhibitor for type 2 diabetes.

Kazano alogliptin/metforminCombination dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide for type 2 diabetes.

Oseni alogliptin/pioglitazoneCombination dipeptidyl peptidase-4 (DPP-4) inhibitor and thiazolidinedione for type 2 diabetes.


http://www.fda.gov/


New Drugs - HyperlipidemiasBrand Generic Description

Kynamro mipomersenAn injectable oligonucleotide inhibitor of apolipoprotein B-100 synthesis for patients with homozygous familial hypercholesterolemia.


http://www.fda.gov/


New Drugs – Hematologic conditions


Bleeding management

Kcentraprothrombin complex concentrate

PCC (human) for urgent reversal of vitamin K antagonist (e.g., warfarin) therapy in adults with acute major bleeding.

Rixubis coagulation factor IXA recombinant factor IX to control or prevent bleeding in adults with hemophilia B.

Iron deficiency anemia

Injectafer ferric carboxymaltose An injectable iron replacement formulation for iron deficiency anemia.


http://www.fda.gov/


New Drugs & Formulations - RespiratoryBrand Generic Description

New Drugs

Opsumit Macitentan Endothelin receptor blocker approved for pulmonary arterial hypertension in adults

Adempas Riociguat

Soluble guanylate cyclase stimulator approved to improve ability to exercise in chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) of unknown causes, inherited or associated with connective tissue diseases

Breo Ellipta fluticasone/vilanterol An inhaled corticosteroid/long-acting beta agonist for COPD.

New formulations

Atrovent Respimat Ipratropium inhaler Reformulated to remove CFCs, soy, used for COPD

Combivent Respimat

Ipratropuim/albuterol inhaler Reformulated to remove CFCs, soy, used for COPD


http://www.fda.gov/


New Formulations – Gastrointestinal Agents


Aciphex Sprinkle rabeprazoleNew 5 mg and 10 mg sprinkle (capsule) formulation for children with GERD.

Esomeprazole Strontium

esomeprazole strontium

New salt form of PPI esomeprazole.

Delzicol mesalamineDelayed-release capsule formulation for ulcerative colitis.

Uceris budesonideNew oral extended-release tablets for ulcerative colitis.

SuclearPEG-3350 plus electrolytes

New osmotic laxative for colon cleansing before colonoscopy.


http://www.fda.gov/


New Drugs & Formulations – Immunomodulatory & Antihistamine AgentsBrand Generic Description

Immunomodulatory

Simponi Aria golimumabAn intravenous tumor necrosis factor (TNF) blocker for rheumatoid arthritis in combination with methotrexate.

Tecfidera dimethyl fumarateAn oral capsule formulation for patients with relapsing forms of multiple sclerosis.

Astagraf XL tacrolimusAn extended-release capsule formulation to prevent organ rejection after a kidney transplant.

Antihistamines & combinations

Karbinal ER carbinoxamineExtended-release suspension formulation antihistamine.

Vituzhydrocodone/ chlorpheniramine

New combination antitussive/antihistamine for cough and allergy or cold symptoms.


http://www.fda.gov/


New Drugs & Formulations - AntineoplasticsBrand Generic Description

New Drugs

Gilotrif afatinib A kinase inhibitor for certain types of metastatic non-small cell lung cancer.

Kadcyla ado-trastuzumab A HER2-targeted antibody and microtubule inhibitor for HER2-positive, metastatic breast cancer.

Mekinist trametinib A kinase inhibitor for advanced melanoma with BRAF V600E or V600K mutations.

Tafinlar dabrafenib A kinase inhibitor for advanced melanoma with BRAF V600E mutation.

Xofigo radium Ra223 dichloride A radioactive agent for advanced prostate cancer with bone metastases.

Pomalyst pomalidomide A thalidomide analogue for multiple myeloma.

New Formulations

Valchlor mechlorethamine A topical gel formulation for cutaneous T-cell lymphoma.


http://www.fda.gov/


New Formulations - TopicalsBrand Generic Description

Mirvaso brimonidineNew topical gel formulation for facial erythema of rosacea.

Topicort desoximetasoneNew topical spray formulation corticosteroid for plaque psoriasis.

Sitavig acyclovirNew buccal tablet formulation for recurrent cold sores.

Simbrinza brinzolamide/brimonidineNew ophthalmic combination formulation containing a carbonic anhydrase inhibitor and an alpha-2 agonist for glaucoma.


http://www.fda.gov/


New Drugs & Formulations – Miscellaneous


Diagnostic Agents

Dotarem gadoterate meglumineA gadolinium-based contrast agent for use with magnetic resonance imaging (MRI).

Lymphoseektechnetium Tc 99m tilmanocept

A radioactive diagnostic imaging agent to help locate tumor-draining lymph nodes in patients with breast cancer or melanoma.

Metabolic Disorders

Ravicti glycerol phenylbutyrateAn oral liquid to help control blood ammonia levels in patients with certain urea cycle disorders.

Urinary conditions

Procysbi cysteamine bitartrateNew delayed-release formulation for nephropathic cystinosis.


http://www.fda.gov/


Pharmacy update What’s new in the world of pharmaceuticals? Petra Eichelsdoerfer, ND, CN, RPh New...

Documents

Transcript of Pharmacy update What’s new in the world of pharmaceuticals? Petra Eichelsdoerfer, ND, CN, RPh New...