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
1
Disclosure
No potential conflict of interest
2
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
3
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
4
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
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
Prescription Drug Monitoring Programs (PMPs)
• 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
Prescription Drug Monitoring Programs (PMPs)
• 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: james.queenan@nh.gov
• 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/
9
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
American Society of Health-System Pharmacy News, www.ashp.org
10
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
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
American Society of Health-System Pharmacy News, www.ashp.org
12
Codeine metabolism
Crews, et al. Clinical Pharmacol Ther. 2012; 91: 321 - 326
13
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 nextmorning impairment.
American Society of Health-System Pharmacy News, www.ashp.org
14
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 possible
Pharmacist’s Letter, www.pharmacistsletter.com
15
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
16
Comparing benzodiazepines (sampling)
Dosage
Drug
range (mg/d)
Alprazolam 0.75 to 4
Peak
plasma
level (h)
1 to 2
Elimination
t1/2 (h)
6.3 to 26.9
Metabolites
Active
Speed of
onset
intermediate
Protein
binding
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%
1–2
1.5 – 5.5
Inactive
fast
Triazolam 0.125 – 0.5
Adapted from: Facts & Comparisons
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 NOT
Pharmacists’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
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 pglycoprotein 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
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
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
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, itraconazole
Facts & Comparisons, http://online.factsandcomparisons.com; US Food and Drug Administration, www.fda.gov
26
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
Pharmacist’s Letter, www.pharmacistsletter.com
27
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
New medications and
Dosage forms
Pharmacist’s Letter; http://pharmacistsletter.therapeuticresearch.com
29
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 & formulations
Women’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 & formulations
Hyperlipidemia 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 removed
32
Summarizing new drugs & formulations
Gastrointestinal 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 & formulations
Topicals
• 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
Pharmacist’s Letter, www.pharmacistsletter.com
36
Diabetes
37
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)
LDL: < 100 mg/dL (2.59 mmol/l)
< 70 mg/dL (1.81 mmol/l) (with overt CVD)
Lipids
HDL: > 40 mg/dL (1.04 mmol/l)
> 50 mg/dL (1.30 mmol/l)
TG:
< 150 mg/dL (1.69 mmol/l)
HDL = high-density lipoprotein; LDL = low-density lipoprotein;
PG = plasma glucose; TG = triglycerides.
Adapted from: ADA. Diabetes Care 2012;35:S11–S63
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
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 1
Diabetes 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
T2DM Anti-hyperglycemic Therapy: General Recommendations
Diabetes Care 2012;35:1364–1379
Diabetologia 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 Ccell tumors (in rodents)
• Note: Bydureon unavailable in a pre-mixed pen (ER formulation)
Facts & Comparisons eAnswers, www.factsandcomparisons.com; Pharmacist’s Letter, www.pharmacistsletter.com
44
Glucagon-like peptide 1 (GLP-1) agonists
(incretin mimetics) in Summary
Exenatide
Byetta
Generic name
Trade name
Dosage forms
Injection, solution:
strengths available
250 mcg/mLa
Exenatide ER
Bydureon
Injection, powder
for suspension,
Liraglutide
Victoza
Injection, solution:
6 mg/mLb
ER: 2 mg
Initial adult dose
Maintenance
adult dose
5 mcg
2 mg
0.6 mg
subcutaneously
subcutaneously
subcutaneously
twice daily
once weekly
once daily
10 mcg
2 mg
1.2 to 1.8 mg
subcutaneously
subcutaneously
subcutaneously
twice daily
once weekly
once daily
• 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 pens
Adapted from: Facts & Comparisons eAnswers, www.factsandcomparisons.com
45
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
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
Facts & Comparisons eAnswers, www.factsandcomparisons.com; Pharmacist’s Letter, www.pharmacistsletter.com
47
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
Pharmacist’s Letter, www.pharmacistsletter.com
48
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
Diabetes – Preventing hypoglycemia
• 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
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
hypoglycemia
Pharmacist’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.
Pharmacist’s Letter, www.pharmacistsletter.com
52
Hypertension,
Hyperlipidemias,
and
Cardiovascular
Disease
53
Hypertension & hyperlipidemias in overview
Blood 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 therapies
Pharmacist’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
Facts & Comparisons eAnswers, www.factsandcomparisons.com; Pharmacist’s Letter, www.pharmacistsletter.com
58
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
Facts & Comparisons eAnswers, www.factsandcomparisons.com; Pharmacist’s Letter, www.pharmacistsletter.com
59
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 - GDMT
Structural 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 antagonist
American 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 recommended
American 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
Cardiovascular Risk
LDL-C Goal
Initiate Lifestyle
Changes
Consider Drug
Therapy
High Risk
< 100 mg/dL (optimal
(existing CHD or CHD
goal: < 70 mg/dL)
equivalents; 10-year risk >
20%)
> 100 mg/dL
> 100 mg/dL
Moderately High Risk
< 130 mg/dL
(2+ risk factors; 10-year risk
10% to 20%)
> 130 mg/dL
> 130 mg/dL
Moderate Risk
< 130 mg/dL
(2+ risk factors; 10-year risk
< 10%)
> 130 mg/dL
> 160 mg/dL
Lower Risk
(0-1 risk factors)
> 160 mg/dL
> 190 mg/dL
< 160 mg/dL
National Cholesterol Education Program (NCEP) Guidelines, 2004
64
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
Facts & Comparisons eAnswers, www.factsandcomparisons.com; Pharmacist’s Letter, www.pharmacistsletter.com
65
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
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
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 dosing
UpToDate, 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 treatment
CDC Health Alert Network, CDCHAN-00349, http://emergency.cdc.gov/HAN/han00349.asp
72
Doxycycline & Tetracycline shortages
Note: 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 rosacea
Milder 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.
Pharmacist’s Letter, www.pharmacistsletter.com
74
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
Pharmacist’s Letter, www.pharmacistsletter.com
75
Alternatives in beta-lactam allergy
Recommendations
• 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 resistance
Pharmacist’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
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, RPh
petraelena@gmail.com
81
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
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
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
New Drugs &
Dosage Forms:
Summary Tables
85
Neurology & Mental Health
Brand
New Drug
Generic
Description
Brintellix
vortioxetine
An SSRI for treatment of depression.
New Formulations
Extended-release injectable formulation for
schizophrenia.
An SNRI for depression. The levo isomer of milnacipran
(Savella).
A new extended-release tablet formulation for
depression.
New oral solution to improve neurological outcomes post
subarachnoid hemorrhage.
Abilify Maintena
aripiprazole
Fetzima
levomilnacipran
Khedezla
desvenlafaxine
Nymalize
nimodipine
Trokendi XR
topiramate
New extended-release capsule formulation for seizures.
Versacloz
clozapine
New oral suspension formulation for schizophrenia.
Zecuity
sumatriptan
Zubsolv
buprenorphine/
naloxone
New iontophoretic transdermal system for acute
treatment of migraine.
New sublingual tablet formulation for maintenance
treatment of opioid dependence.
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
86
New Drugs & Formulations – Infectious
Disease
Generic
Brand
New Drugs
BAT
Description
botulism antitoxin
Immune globulin fragments for treatment of
heptavalent (equine) 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
dolutegravir
An integrase strand transfer inhibitor for HIV-1
infection.
New Formulation
TOBI
Podhaler
tobramycin
New oral inhalation powder formulation for cystic
fibrosis patients with Pseudomonas aeruginosa
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
87
New Drugs – Women’s Health
Description
Combination estrogen/SERM for
conjugated
menopausal vasomotor symptoms and
Duavee
estrogen/bazedoxifene
prevention of postmenopausal osteoporosis.
An oral estrogen agonist/antagonist for
painful sexual intercourse due to
Osphena ospemifene
menopause.
Brand
Generic
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
88
New Formulations – Women’s Health
Brand
Generic
Description
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.
levonorgestrel/ethinyl estradiol
New 84-day extended-cycle oral
contraceptive with gradually increasing
doses of estrogen.
levonorgestrel
New progestin-containing intrauterine
system for prevention of pregnancy for up
to three years.
doxylamine/pyridoxine
A combination antihistamine/vitamin B6
for pregnancy-related nausea and
vomiting.
Oxytrol for Women
oxybutynin
New 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.
Quartette
Skyla
Diclegis
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
89
New Drugs - Diabetes
Generic
Description
Invokana
canagliflozin
A sodium-glucose co-transporter 2 (SGLT2)
inhibitor to increase glucose excretion in
patients with type 2 diabetes.
Nesina
alogliptin
New dipeptidyl peptidase-4 (DPP-4) inhibitor for
type 2 diabetes.
Kazano
alogliptin/metformin
Combination dipeptidyl peptidase-4 (DPP-4)
inhibitor and biguanide for type 2 diabetes.
alogliptin/pioglitazone
Combination dipeptidyl peptidase-4 (DPP-4)
inhibitor and thiazolidinedione for type 2
diabetes.
Brand
Oseni
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
90
New Drugs - Hyperlipidemias
Brand
Generic
Description
Kynamro
An injectable oligonucleotide inhibitor of apolipoprotein Bmipomersen 100 synthesis for patients with homozygous familial
hypercholesterolemia.
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
91
New Drugs – Hematologic
conditions
Brand
Generic
Description
Bleeding management
Kcentra
prothrombin complex
concentrate
PCC (human) for urgent reversal of vitamin K
antagonist (e.g., warfarin) therapy in adults with
acute major bleeding.
Rixubis
coagulation factor IX
A 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.
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
92
New Drugs & Formulations - Respiratory
Generic
Description
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.
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
Brand
New Drugs
Opsumit
New formulations
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
93
New Formulations –
Gastrointestinal Agents
Brand
Generic
Aciphex Sprinkle rabeprazole
Description
New 5 mg and 10 mg sprinkle (capsule)
formulation for children with GERD.
Esomeprazole
Strontium
esomeprazole
strontium
New salt form of PPI esomeprazole.
Delzicol
mesalamine
Delayed-release capsule formulation for
ulcerative colitis.
Uceris
budesonide
Suclear
PEG-3350 plus
electrolytes
New oral extended-release tablets for
ulcerative colitis.
New osmotic laxative for colon cleansing
before colonoscopy.
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
94
New Drugs & Formulations –
Immunomodulatory & Antihistamine Agents
Brand
Generic
Description
Immunomodulatory
Simponi Aria golimumab
An intravenous tumor necrosis factor (TNF)
blocker for rheumatoid arthritis in combination
with methotrexate.
Tecfidera
dimethyl fumarate
An oral capsule formulation for patients with
relapsing forms of multiple sclerosis.
Astagraf XL
tacrolimus
An extended-release capsule formulation to
prevent organ rejection after a kidney transplant.
Antihistamines & combinations
Karbinal ER
carbinoxamine
Extended-release suspension formulation
antihistamine.
Vituz
hydrocodone/
chlorpheniramine
New combination antitussive/antihistamine for
cough and allergy or cold symptoms.
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
95
New Drugs & Formulations - Antineoplastics
Generic
Description
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.
Brand
New Drugs
New Formulations
Valchlor
mechlorethamine
A topical gel formulation for cutaneous T-cell lymphoma.
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
96
New Formulations - Topicals
Brand
Generic
Description
Mirvaso
brimonidine
New topical gel formulation for facial erythema
of rosacea.
Topicort
desoximetasone
New topical spray formulation corticosteroid for
plaque psoriasis.
Sitavig
acyclovir
New buccal tablet formulation for recurrent cold
sores.
Simbrinza
New ophthalmic combination formulation
brinzolamide/brimonidine containing a carbonic anhydrase inhibitor and
an alpha-2 agonist for glaucoma.
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
97
New Drugs & Formulations – Miscellaneous
Brand
Generic
Description
Diagnostic Agents
Dotarem
gadoterate meglumine
Lymphoseek
technetium Tc 99m
tilmanocept
A gadolinium-based contrast agent for use with
magnetic resonance imaging (MRI).
A radioactive diagnostic imaging agent to help
locate tumor-draining lymph nodes in patients
with breast cancer or melanoma.
Metabolic Disorders
Ravicti
An oral liquid to help control blood ammonia
glycerol phenylbutyrate levels in patients with certain urea cycle
disorders.
Urinary conditions
Procysbi
cysteamine bitartrate
New delayed-release formulation for
nephropathic cystinosis.
Adapted from US Food and Drug Administration, www.fda.gov; Pharmacist’s Letter, www.pharmacistsletter.com
98