New Drugs of 2007
Part 1
Presented by: Sara Tebbe, PharmD
Drugs Covered: aliskiren (Tekturna®)
ambrisentan (LetairisTM)
amlodipine/olmesartan (Azor®)
eculizumab (Soliris®)
lidocaine (ZingoTM)
Aliskiren
Tekturna ®
Manufactured by: Novartis
www.prescribingreference.com
Aliskiren (Tekturna®)
Therapeutic Class
• Antihypertensive: Renin Inhibitor
Indications
• Hypertension alone or in combination with other
antihypertensive agents
Tekturna® (Aliskiren) Package Insert. East Hanover, NJ: Novartis. September 2007.
Aliskiren (Tekturna®)
Mechanism of action Pharmacokinetics
Decreases the plasma • Absorption: Bioavailability of
renin activity (PRA); ~ 2.5%. With a high fat meal,
which is responsible for mean AUC & Cmax are
converting decreased by 71% and 85%
angiotensinogen to
angiotensin I • Distribution: Steady state
reached at 7-8 days
• Metabolism: CYP3A4 enzyme
• Elimination: Approximately ¼
appears in the urine as parent
drug; unknown how much of the
absorbed dose is metabolized
Tekturna® (Aliskiren) Package Insert. East Hanover, NJ: Novartis. September 2007.
Aliskiren (Tekturna®)
www.uspharmacist.com
Aliskiren (Tekturna®)
Dosing and Administration
• Starting dose of aliskiren is 150 mg PO daily
• Dose may be increased to a max of 300 mg PO daily
Cost
• ~ $1.89 for 150 mg tab and $2.38 for 300 mg tab
Patient Education
• Potential to cause hypotension
• Medication should be taken at the same time daily
• If patient forgets to take medication, take it as soon as
remembered; do not double dose
• Medication should NOT be administered with a high fat
meal
Tekturna® (Aliskiren) Package Insert. East Hanover, NJ: Novartis. September 2007.
Aliskiren (Tekturna®)
Contraindications & Precautions
• Pregnancy category: C - first trimester; D - second and third trimesters
• Caution in patients with severe renal dysfunction
• Concurrent use of ACE-Inhibitor or ARB and the risk of hyperkalemia
Drug Interactions
• Co-administration of irbesartan reduced the Cmax of aliskiren by ~ 50%
• Co-administration of atorvastatin results in a 50% increase in the Cmax
and AUC of aliskiren after multiple dosing
• Co-administration of ketoconazole results in an 80% increase in plasma
levels of aliskiren
• Co-administration of furosemide results in a 30% reduction of AUC and
50% reduction of Cmax of aliskiren
Adverse Effects
Angioedema, other edema (face, hands, whole body), diarrhea,
abdominal pain, dyspepsia, hyperkalemia and cough
Tekturna® (Aliskiren) Package Insert. East Hanover, NJ: Novartis. September 2007.
Aliskiren (Tekturna®)
Objective To evaluate BP lowering effects of aliskiren, alone or in combination
with valsartan (primary efficacy change in mean diastolic BP)
Design Multicenter, randomized, placebo-controlled, 8-week trial
Study 1123 patients with mild to moderate HTN underwent a 3 to 4 week
Arms single-blind placebo run-in and then randomized to treatment groups.
Patients received once-daily, double-blind oral treatment with
placebo; aliskiren monotherapy (75, 150, or 300 mg), valsartan
monotherapy (80, 160, or 320 mg), aliskiren and valsartan in
combination, or valsartan/HCTZ (160/12.5 mg)
Results Aliskiren 300 mg significantly (p3 times the ULN.
Conclusion Ambrisentan increases exercise capacity, improves symptoms of
PAH, and improves hemodynamics with a low incidence of liver
abnormalities.
Galie N, et al. J Am Coll Card. 2004; 43(12):5S-12S.
6-MWD: 6-minute walk distance
Ambrisentan (Letairis™)
Place in Therapy
• Add on agent for the treatment of pulmonary
arterial hypertension (following treatment with
CCBs and/or sildenafil)
• May be used as monotherapy or with other
agents to treat PAH
Clinical Pearls
• Minimal liver abnormalities as compared to
bosentan
CCB: calcium channel blocker
Amlodipine/Olmesartan
Azor®
Manufactured by: Daiichi-Sankyo
www.prescribingreference.com
Amlodipine/Olmesartan (Azor®)
Therapeutic Class
• Anti-hypertensive: Calcium Channel Blocker
(CCB) and Angiotensin II Receptor Blocker (ARB)
Indications
• Hypertension alone or with other antihypertensive
agents
Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.
Amlodipine/Olmesartan (Azor®)
Mechanism of action
• Amlodipine works by inhibiting the
transmembrane influx of calcium ions in
cardiac and vascular smooth muscle
• Olmesartan inhibits the vasoconstrictor effects
of angiotensin II
Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.
Amlodipine/Olmesartan (Azor®)
Pharmacokinetics (amlodipine) Pharmacokinetics (olmesartan)
• Absorption: Bioavailability ~
64% to 90% • Absorption: Bioavailability ~ 26%
• Distribution: ~ 93% bound to • Distribution: Highly bound to
plasma proteins, reaches steady- plasma proteins (99%); reaches
state in 7-8 days steady-state in 3-5 days
• Metabolism: ~ 90% is • Metabolism: Olmesartan
converted to inactive metabolites medoxomil converted to
via hepatic metabolism olmesartan during absorption and
no further metabolism of
• Elimination: 10% (parent
olmesartan
compound) and 60%
(metabolites) are excreted in the • Elimination: 35%-50% is
urine; effective half-life of ~ 45 eliminated in the feces; effective
hours half-life of ~ 7 hours
Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.
Amlodipine/Olmesartan (Azor®)
Dosing and Administration
• Initiate at 5/20 mg PO daily and titrate to desired BP goal
• Available as 5/20, 5/40, 10/20 or 10/40 mg tablets
Cost
• Between $1.86 and $2.68 per tablet
Patient Education
• Potential to cause hypotension
• Take this medication at the same time each day
• If patient forgets to take medication take it as soon as
remembered; do not double dose
Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.
Amlodipine/Olmesartan (Azor®)
Contraindications & Precautions
• Pregnancy category: C - first trimester; D - second through
third trimesters
• Caution in severe renal and/or hepatic dysfunction
• Concurrent use of ACE-I or ARB and risk of hyperkalemia
• Caution in patients with severe obstructive coronary artery
disease or congestive heart failure
Drug Interactions
• No clinically significant drug interactions
Adverse Effects
• Edema, dizziness, palpitation, and flushing
Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.
Amlodipine/Olmesartan (Azor®)
Objective To determine if amlodipine/olmesartan was associated with
significant ↓ in BP compared to the respective monotherapy
Design 8-week, multicenter, randomized, double-blind, placebo-controlled,
parallel-group factorial 8-week study
Study Arms 1923 patients were randomized to one of twelve treatment arms:
placebo, monotherapy with amlodipine 5 mg or 10 mg,
monotherapy with olmesartan 10 mg, 20 mg, or 40 mg, or
combination therapy amlodipine/olmesartan 5/10 mg, 5/20 mg,
5/40 mg, 10/10 mg, 10/20 mg and 10/40 mg
Results Significantly greater reductions in diastolic and systolic BP
compared to respective monotherapy components
Conclusion Combination therapy is more effective at treating hypertensive
patients than either therapy alone
Azor® (amlodipine/olmesartan) Package Insert. Parsippany, NJ: Daiichi-Sankyo. December 2007.
Amlodipine/Olmesartan (Azor®)
Place in Therapy
• This combination product may be appropriate for
patients who desire a smaller pill burden
• May also be used as an add-on anti-hypertensive
medication
Clinical Pearls
If compliance is an issue or if this agent is cheaper
through insurance, amlodipine/olmesartan may be
beneficial to the patient.
Eculizumab
Soliris ®
Manufactured by: Alexion Pharmaceuticals
www.prescribingreference.com
Eculizumab (Soliris®)
Therapeutic Class
• Monoclonal antibody
Indications
• Paroxysmal nocturnal hemoglobinuria (PNH)
Soliris® (eculizumab) Package Insert. Chesire, CT: Alexion. June 2007.
Eculizumab (Soliris®)
Mechanism of action Pharmacokinetics
Monoclonal antibody • Distribution: Volume of
that specifically binds distribution ~ 7.7 L
to and inhibits the • Elimination: Half life
terminal complement ~ 272 ± 82 hours
mediated intravascular
hemolysis in PNH
patients
www.soliris.net
Soliris® (eculizumab) Package Insert. Chesire, CT: Alexion. June 2007.
Eculizumab (Soliris®)
Dosing and Administration
• 600 mg every 7 days for 4 weeks, followed by
• 900 mg for the fifth dose 7 days later, then
• 900 mg every 14 days thereafter
Cost
• 300mg vial is ~ $4992
Patient Education
• Patients must be vaccinated against meningococcus
• Potential for serious hemolysis when eculizumab is
discontinued
Soliris® (eculizumab) Package Insert. Chesire, CT: Alexion. June 2007.
Eculizumab (Soliris®)
Contraindications & Precautions
• May have an increased susceptibility to infections
• May result in infusion reactions
• Pregnancy category C
Drug Interactions
• No drug interactions have been studied or reported
Adverse Effects
• Meningococcal infections, headache, back pain,
nausea, fatigue and cough
Soliris® (eculizumab) Package Insert. Chesire, CT: Alexion. June 2007.
Eculizumab (Soliris®)
Objective To investigate if eculizumab stabilized hemoglobin levels and
reduced transfusion requirements
Design Double-blind, randomized, placebo-controlled, multi-center, phase-3
Study 44 patients received eculizumab IV 600 mg weekly x 4 weeks, 900
Arms mg x 1 week, and then 900 mg every other week through week 26;
while 43 patients received placebo
Results Hemoglobin stabilization was achieved in 49% of eculizumab
patients and 0% on placebo (p placebo) – drowsiness
(6%), nasopharyngitis (6%), fatigue (2%), dry mouth (3%),
and pharyngitis (subjects ≥12 years old) and pyrexia (4%),
drowsiness (3%), cough (3%), and epistaxis (2%) (children
6-12 years old)
Xyzal™ [Package Insert]. Bridgewater, NJ: 2007.
Levocetirizine dihydrochloride (Xyzal®)
Potter PC. Ann Allergy Asthma Immunol 2005;95:175-80.
Objective Evaluate effect of levocetirizine on the total 4 symptom score, the 50%
response rate, the Pediatric Rhinitis Quality of Life Questionnaire
(PRQLQ), and investigators’ global evaluation of symptom management
Design Double-blind, placebo-controlled, randomized, multicenter clinical trial
(n=306)
Study Randomized to levocetirizine 5mg once daily for 4 weeks (n=154) or
Arms placebo (n=152). Patients completed daily diary cards, and the PRQLQ
and investigators’ global evaluations were conducted at 3 visits.
Results Levocetirizine group had significant improvement in 2-week and 4-week
Total 4 Symptom Score compared to placebo. The 50% response rate for
the first 2 weeks: Levocetirizine 12.3% vs. placebo 3.9% (P=0.01).
Investigators’ global evaluation favored levocetirizine vs. placebo.
Levocetirizine provided significantly greater HRQL improvement than
placebo at 2 weeks (P=0.01). Adverse events did not differ between the 2
groups.
Conclusion Levocetirizine, at a dose of 5mg once daily, is an effective and safe
treatment in relieving symptoms of PAR in children aged 6-12 years
Levocetirizine dihydrochloride (Xyzal®)
Caronica GW, et al. Respiratory Medicine. 2006;100:1706-15.
Objective Determine whether long-term treatment with levocetirizine 5mg improves
Health-related Quality of Life (HRQOL) and health status in persistent
allergic rhinitis (PER) patients assessed with the Rhinoconjuctivitis Quality
of Life Questionnaire (RQLQ) and SF-36 scales over a 6-month period
Design Levocetirizine in PER Study (XPERT) was a multicenter, double-blind,
parallel group study (n=551)
Study Randomized to either levocetirizine 5mg once daily for 6 months or
Arms placebo. Assessed for symptoms, HRQOL, RQLQ and health status (SF-
36)
Results Levocetirizine showed statistically significant improvements vs. placebo.
Relative improvement of levocetirizine over placebo exceeded the
predefined clinically meaningful threshold
Conclusion This study expands the results of the XPERT study – Long-term treatment
with levocetirizine provides sustained improvement of HRQOL and
reduces disease burden in PER patients
Levocetirizine dihydrochloride (Xyzal®)
Place in Therapy
For patients with seasonal and perennial
allergic rhinitis or uncomplicated skin
manifestations of chronic idiopathic urticaria
who may get too sleepy with cetirizine or other
histamine blockers
Xyzal™ [Package Insert]. Bridgewater, NJ: 2007.
Retapamulin
Altabax™
Manufactured by: GlaxoSmithKline
www.prescribingreference.com
Retapamulin (Altabax™)
Therapeutic Class
• Antibacterial agent
Indications
• For use in patients ≥ 9 months for the topical
treatment of impetigo due to Staphylococcus
aureus (methicillin-susceptible isolates only) or
Streptococcus pyogenes
Altabax ™ [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007.
Retapamulin (Altabax™)
Mechanism of action Pharmacokinetics
• Semisynthetic • Absorption: Low
derivative of systemically
pleuromutilin • Distribution: ~ 94%
• Inhibits peptidyl bound to human plasma
transfer, blocks P- proteins. VD has not been
site interactions, and determined
prevents the normal • Metabolism: CYP3A4
creation of active • Elimination: Unknown
50S ribosomal
subunits • Dose Adjustments:
None
Altabax ™ [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007.
Retapamulin (Altabax™)
Dosing and Administration
• Apply a thin layer to the affected area twice daily for 5 days
Cost
Cost: 5gm $48.25; 10gm $72.61; 15gm $88.78 (AWP)
Patient Education
• Wash hands after application
• For external use only
• Use the medication for the full time recommended by the
healthcare provider
• If no improvement in symptoms within 3 to 4 days of starting
therapy, notify the healthcare provider
• May cause reactions at the site of application
Altabax ™ [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007.
Retapamulin (Altabax™)
Contraindications and Precautions
• Contraindications - none
• Local irritation
• Potential for microbial overgrowth
• Pregnancy category B
Drug Interactions
• Oral ketoconazole
• Unlikely to affect the metabolism of other P450 substrates
• Effect of concurrent application of retapamulin and other topical
products to the same area of skin has not been studied
Adverse Effects
• Most common (≤2%) – application site irritation
• Other (<1%)– application site pain, erythema, and contact
dermatitis
Altabax ™ [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007.
Retapamulin (Altabax™)
Altabax ™ [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007
Objective Evaluate safety and efficacy of retapamulin
Design Double-blind, randomized, placebo-controlled study (n=210)
Study Arms Patients randomized (2:1) to retapamulin or placebo applied twice daily
for 5 days
Results Success rates by population for pts receiving retapamulin compared with
those receiving placebo were: Clinical per protocol (PPC): 89.5 vs. 53.2%,
Intention to treat clinical (ITTC): 85.6 vs. 52.1%, Bacteriological per
protocol (PPB): 89.7 vs. 50%, Intention to treat bacteriological (ITTB):
88.6 vs. 49.1%. At follow-up, 9 days after treatment, success rates were:
PPC: 82.4 vs. 43.1%, ITTC: 75.5 vs. 39.4%, PPB: 84.3 vs. 37.5%, ITTB:
79.8 vs. 33.3%
Conclusion Retapamulin is a safe and effective topical treatment for impetigo
Retapamulin (Altabax™)
Oranje, AP, et al. Dermatology 2007;215:331-40.
Objective Compare efficacy and safety of retapamulin to sodium fusidate in treating
impetigo
Design Multi-center, randomized, observer-blinded, noninferiority, comparative,
phase III study (n=519)
Study Arms Subjects randomly assigned (2:1) to retapamulin 1% twice daily for 5 days
or sodium fusidate 2% three times daily for 7 days
Results Retapamulin (n=346), sodium fusidate (n=173). Both had comparable
clinical efficacies - Per-protocol population: 99.1 and 94%, respectively;
difference: 5.1%, 95% CI – 1.1-9%, p=0.003. Intention to treat population:
94.8 and 90.1%, respectively; difference: 4.7%, 95% CI: -0.4-9.7%,
p=0.062. Bacteriological efficacies similar - Per-protocol population:
98.3% in retapamulin group and 93.9% in sodium fusidate group. Both
drugs well tolerated.
Conclusion Retapamulin is an effective and convenient new treatment for impetigo
Retapamulin (Altabax™)
Place in Therapy
For patients who would prefer a twice daily
regimen opposed to a three times daily
regimen for the topical treatment of impetigo
Clinical Pearls
• Believed to have no resistance patterns
Altabax ™ [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2007.
Learning Assessment
Question Time!
A patient with central precocious puberty is about to
receive an injection of histrelin. She also has moderate
renal impairment. This is a problem because
a) The dose of histrelin will have to
be decreased.
b) Histrelin is contraindicated in
patients with renal impairment.
c) There is no problem. There is no
dosage adjustment for histrelin.
d) The dose of histrelin will have to
be increased.
A patient with seasonal allergic rhinitis. He has tried
fexofenadine, diphenhydramine, and cetirizine with no
success. Another antihistamine option may be
a) Dextrocetirizine
b) Levocetirizine
c) Levothyroxine
d) Flonase
A patient on the Lanreotide injection is taking the
following medications: cyclosporine, aspirin,
docusate, and fexofenadine. Which of the patient’s
medications could interact with the Lanreotide?
a) Cyclosporine
b) Aspirin
c) Docusate
d) Fexofenadine
Retapamulin ointment, 1%, is a pleuromutilin
antibiotic. The advantage it has over other
treatments available is that
a) It is applied 4 times daily
b) It is applied 2 times daily
c) It is applied once daily
d) It is applied 3 times daily
A patient in the hospital is having severe vasomotor
symptoms associated with menopause. Her past
medical history is significant for breast cancer. She
doesn’t like the estradiol patch because it irritates her
skin. Thus, her order for the estradiol transdermal
spray would be a good option.
a) TRUE
b) FALSE
A 10 year old patient with impetigo walks into the
dermatologist’s office. Upon further investigation, it
was known that he has a case caused by S.
pyogenes. What could the dermatologist prescribe
for this patient?
a) Retapamulin ointment
b) Histrelin acetate
c) Neosporin
d) Azithromycin
A disadvantage of the estradiol transdermal spray is that
a) It is not an effective
treatment for severe
vasomotor symptoms due
to menopause
b) You can not take it on an
empty stomach
c) It could require dosing up
to three sprays per day
d) You have to dose adjust
in renal impairment
patients
An acromegalic patient is about to start the
Lanreotide injection. The patient has severe hepatic
impairment and therefore his initial dose would be
a) 50mg every 4 weeks
b) 60mg every 2 weeks
c) 60mg every 4 weeks
d) 50mg every 2 weeks
The greatest advantage that histrelin has over it’s
comparative therapies for the treatment of central
precocious puberty is that
a) It’s inexpensive
b) It is dosed monthly
c) It is dosed yearly
d) There are no comparative
therapies. Histrelin is the
only treatment for central
precocious puberty
available on the market.
A patient with end-stage renal disease has a
prescription for Xyzal 5mg PO daily. You, as the
pharmacist, know you need to call the physician and
recommend that
a) The dose needs to be
reduced to 2.5mg daily
b) The dose needs to be
reduced to 2.5mg twice
weekly
c) Xyzal not be used since it is
contraindicated in patients
with a creatinine clearance of
<10 mL/min
d) The dose should be
increased
Questions?
Brandi Polder, PharmD
The Methodist Hospital
6565 Fannin Street, DB1-09
Houston, TX 77030
blpolder@tmhs.org