New Parenteral Drugs and Biologicals 2008 NHIA Annual Conference

Transcription

New Parenteral Drugs and
Biologicals 2008
A Review for Home and Ambulatory Care Practitioners
NHIA Annual Conference
March 1, 2009
Anna Nowobilski-Vasilios PharmD MBA FASHP BCNSP
1/90
“New Drugs” Memory Lane
60
50
40
30
20
10
0
2001
2002
FDA Approvals
2003
2004
2005
New Molecular Entities
Pharmacist’s Letter. New Drugs Approved by the FDA 2008.
New Drugs and Biologicals presentations, NHIA Annual Meetings, 2002-2008.
2006
2007
Biologicals
2008
Parenterals
2/90
New Drug Approvals 2008
January (7): ciclesonide, rh-thrombin,
etravirine, somatropin, amoxicillin,
fosaprepitant
February (4): niacin-simvastatin,
rilonacept, desvenlafaxine, rantihemophilic factor
March (2): levoleucovorin,
bendamustine
April (6): rotavirus vaccine,
regadenoson, olopatadine,
sumatriptan-naproxen, certolizumab
pegol, methylnaltrexone bromide
May (2): alvimopan, r-Factor VIIa
June (5): triamcinolone acetonide, DTPPolio-H.influenzae vaccine,
metformin-repaglinide, difluprednate,
DTP-Polio vaccine
July (1): gadoxetate
August (3): clevidipine, tetrabenazine,
romiplostim
September (2): granisetron patch,
lobenguane sulfate I 123
October (6): silodosin, C1 inhibitor
(human), benzoyl peroxide &
clindamycin topical, lacosamide,
mesalamine, fesoterodine
November (3): rufinamide,
eltrombopag, tapentadol
December (7): synthetic conjugated
estrogen, adapalene & benzoyl
peroxide, plerixafor, zolpidem
tartrate, gadofosveset trisodium,
bimatroprost, degarelix
(47) New Approvals
(21) New Molecular Entities
Pharmacist’s Letter, New Drugs Approved by the FDA in 2008
Drug Information Online. www.drugs.com
(6) New Biologicals (28%)
(14) New Parenterals (67%)
3/90
Learning Objectives
• Highlight the pathophysiology and therapeutic goals for
each corresponding disease state.
• Discuss the indications and appropriate role of each new
agent.
• Describe the major adverse effects, contraindications,
and precautions for new agent.
• List issues relating to dosing, administration, and storage
for each new agent.
• Discuss patient education and monitoring interventions
that would lead to achievement of therapeutic goals.
4/90
Review of Systems 2008
SYSTEM
DRUG
HEENT
Pulmonary
Cardiac
GI
GU
OB-GYN
Neurology
Musculoskeletal
Rheum/Imm
Endocrine
Hematology
Oncology
Derm
Psych
Other
clevidipine for severe hypertension
certolizumab for Crohn’s disease **
methylnaltrexone for opioid constipation **
lacosamide for partial onset seizures
C-1 inhibitor for prevention of angioedema attacks
somatropin for GHD &Turner Syndrome
Factor VII for bleeding disorders
r-Antihemophilic Factor for bleeding disorders
romiplostim for ITP
rilonacept for cryopyrin-associated syndromes
bendamustine for CLL and NHL **
plerixafor for autologous stem cell transplantation
degarelix for prostate cancer
fosaprepitant for chemotherapy-induced NV
levoleucovorin for MTX rescue **
DTP-Polio vaccine
DTP-Polio-H.influenzae vaccine
Key: Infusion ~ Injection
** Anticipated in 2007 to be approved in 2008.
5/90
Pulmonology
Pulmonology
PAH News
6/90
Pulmonology News
News
• Epoprostenol
• Approved for long-term IV treatment of
primary pulmonary hypertension and
pulmonary hypertension associated with
scleroderma
• Lyophilized powder
• Stable 24hr RT when reconstituted with SWI
or NSS
• Other epoprostenol products require special
diluent and gel packs to maintain 24h stability
Drug Information On Line, www.drugs.com.
NOTE: this product is a generic formulation and has not been assigned a brand name.
7/90
Cardiology
Cardiology
Severe Hypertension
8/90
Approved 8/1/2008
Cardiology – Severe HTN
clevidipine
IV
CleviprexTM
• Dihydropyridine calcium channel blocker (emulsion)
• 2nd IV CCB w/ shorter t½ than nicardipine
• Urgent TX of hypertensive crisis
• In ICU, OR and ED
• Goal: reduce BP quickly and avoid hypotension leading to MI,
stoke, vision loss
• Other agents: nitroprusside, nicardipine, fenoldopam,
nitroglycerine, phentolamine, esmolol, labetolol,
hydralazine
• Safety profile similar to nitroglycerine, nitroprusside, and
nicardipine in 1964 patients undergoing cardiac surgery
• ADR’s: hypotension, reflex tachycardia
• Alternative to older agents for perioperative or acute
severe hypertension.
• Monitor: BP, HR during infusion and until VS stabilized
The Medical Letter 2008; 50(1295):73.
Cleviprex™ (clevidipine) [package insert]. Parsippany NJ: The Medicines Company; August 2008.
9/90
Gastroenterology
Gastroenterology
Crohn’s Disease
Opioid Constipation
10/90
Gastroenterology
Crohn’s Disease
• Pathophysiology
• Chronic transmural inflammatory bowel disease
• Leads to fibrosis and obstructive symptoms
• Can affect any part of the GIT from mouth to anus.
• Prevalence: 1M WW; M:F = 1.1-1.8:1
• Incidence of colonic Crohn’s disease has increased
over the last 50 years (northern climates)
• Morbidity & Mortality
• Diarrhea, fever, rectal bleeding malnutrition, intestinal
tract narrowing, obstructions, abscesses, cramping,
abdominal pain, fistulas
• No to 5-fold increased risk of death
Pharmacist's Letter/Prescriber's Letter 2008;24(6):240607.
FDA News. April 22, 2008.
E-Medicine. www.emedicine.medscape.com. July 18, 2007.
11/90
Gastroenterology
Crohn’s Disease
• Treatment Options
• Aminosalicylates (mesalamine, sulfasalazine)
• Corticosteroids (prednisone)
• Immunomodulators (azathioprine, 6-MP,
methotrexate, cyclosporine)
• TNF blockers (infliximab, adalimumab … and …
certolizumab)
• Other: natalizumab
• Goals
• Achieve/maintain remission
• Improve QOL
• Minimize toxicity and complications
E-Medicine. www.emedicine.medscape.com. July 18, 2007.
12/90
Gastroenterology – Crohn’s Disease
Approved 4/22/2008
certolizumab pegol
SQ
Cimzia®
• Moderate to severe Crohn’s disease
• MOA: TNF blocker
• Humanized
• First pegylated TNF blocker
• Blocks inflammatory cascade
• Unlike infliximab and adalimumab, doesn’t induce:
• Complement-activated cytotoxicity
• Antibody-dependent T-cell mediated cytotoxicity
• Apoptosis
• 2 injections q 4wks by healthcare provider
• Adalimumab self-injected q 2 wks
• Infliximab infused
FDA News, April 22, 2008.
The Medical Letter 2008; 60(1297):81-2.
Cimzia® (certolizumab pegol) [package insert]. Smyrna GA: UCB, Inc. April 2008.
13/90
certolizumab pegol
Clinical Trials
• Dose-response study1
• 292 pts: certolizumab 100, 200, 400 mg vs placebo @ wk 0, 4, 8.
• Onset of effect 2 wks; Greater efficacy at 400 mg
• Clinical response seen in certolizumab vs placebo @ wk 2, 4, 8,
10.
• Wk 12 % w/ clinical response not stat different betw certolizumab
400mg & placebo.
• PRECiSE 1: DBRPC (Rochester MN)2
• 659 adult pts: certolizumab vs placebo x 24 weeks (wk 0, 2, 4 &
q4wks)
• Week 6: response 35% vs 27%; remission NSS
• Week 26: response 37% vs 27%; remission NSS
• Serious adverse effects: 10% vs 7%; antibody development 8%
• Remission rates not significantly higher with certolizumab
1.
2.
Schreiber S, Rugeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol
(CDP870) for treatment of Crohn’s disease. Gastroenterology 2005; 129(3):807-18.
Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. NEJM
2007; 357(3):228-38.
14/90
certolizumab pegol
Clinical Trials
• PRECiSE 2: DBRPC, treatment withdrawal
(Germany)
• 668 adult pts: certolizumab 400mg wk 0, 2, 4
• 428 responders (64%): certolizumab vs placebo wks 8 thru
24
• Week 26: response 63% vs 36%; remission 48% vs 29%
• Serious adverse effects: 3% vs <1%; antibody 8%
• WELCOME study
• 539 pts: certolizumab in infliximab-intolerant
• Week 6: 62% achieved response; 30% achieved remission
• No head-to-head trials against infliximab or
adalimumab
Schreiber S, Khalig-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease.
NEJM 2007; 357(3):239-50.
15/90
certolizumab pegol
Safety
ADR’s
Precautions
•
•
•
•
•
Respiratory tract infection (20%
vs 13% placebo)
Urinary tract infection (7% vs 6%
placebo)
Arthralgia (6% vs 4% placebo)
Injection site reactions
DI’s
•
Combo w/ anakinra (Kineret®) not
recommended
•
•
•
•
•
• increased risk of serious
infection
•
•
Do not co-administer live or
attenuated vaccines
May elevate aPTT test results
•
•
•
Opportunistic infections (TB,
fungal)
Do not start during active infection
Monitor HBV carriers, D/C and
treat HBV reactivation
Lymphoma, malignancies, &
hematological reactions w/ TNF’s
Anaphylaxis
Exacerbation of neurological,
hematological disorders & heart
failure
Pregnancy Category B
Use in Peds not established
Caution in Elderly
16/90
certolizumab pegol
Administration
Storage & Prep
Dosing
• 200mg lyophilized
powder
• Reconst w/ 1ml SWI
• 2 doses/package
• Reconstitution by health
care professional
• 400mg SC at week 0, 2
and 4
• Administered by a health
care professional
• If response, continue
400mg SC q4wks
• Ea syringe into separate
sites on abdomen or
thigh
• Clear to opalescent,
colorless to pale yellow
solution
• Stability: 2hrs at RT, 24
hours refrigerated
• Do not freeze
• Bring to RT prior to admin
17/90
certolizumab pegol
Care Plan Highlights
• Assess & Monitor
• s/s infection; s/s heart failure
• TB & HBV status
• CBC/diff
• Notes
•
•
•
•
Long-term malignancy or serious infection unclear
FDA required Medication Guide w/ EACH dose
‘step-up’ vs ‘top-down’ controversy
Cost comparison
• Adalimumab $1500/month
• Infliximab $1100/month (70kg)
• Certolizumab $1500/month
• Under investigation in rheumatoid arthritis, plaque psoriasis
The Medical Letter 2008; 60(1297):81-2.
www.ClinicalTrials.gov.
18/90
Gastroenterology
Opioid Constipation
• Pathophysiology
• Opioid tolerance
• Analgesia, respiratory depression & other CNS
effects
• NOT to constipation
• Decreased GI motility with chronic opioids
• Prevalence
• Inevitable in palliative care cancer patients
• May be more uncomfortable than the pain
The Medical Letter 2008: 50(1292):63.
19/90
Gastroenterology
Opioid Constipation
• Prophylaxis Options
• Regularly scheduled stimulant laxatives (senna or
bisacodyl) with stool softener (i.e. docusate)
• Increase laxative doses when opioid is titrated upward.
• Methadone and fentanyl are thought to be less
constipating than other opioids.
• Stimulant laxatives, osmotic laxatives (i.e. lactulose,
PEG), saline laxatives (i.e. MOM), enemas, manual
disimpaction
• Sodium phosphate laxatives are CI’d in renal or heart
failure
• Bulk-forming laxatives are CI’d in patients unable to
drink fluids
The Medical Letter 2008: 50(1292):63.
20/90
Gastroenterology – Opioid Constipation
Approved 4/24/2008
methylnaltrexone bromide
SQ
Relistor®
• Selective mu-opioid receptor antagonist
similar to naltrexone
• Methyl group keeps it from crossing BBB
• Allows for blocking peripheral and not central mu
receptors
• Indicated in pts on chronic palliative opioid
therapy with opioid-induced constipation who
are not helped by laxatives
• Use >4 mo not studied
• Not a controlled substance
The Medical Letter 2008;50(1292):63.
Resistor® (methylnaltrexone) [package insert]. Philadelphia PA and Tarrytown NY: Wyeth Pharmaceuticals and
Progenics Pharmaceuticals; April 2008.
21/90
methylnaltrexone
Clinical Trials
• 2 RDBPC trials
•
•
•
•
287 patients over 4 months
Advanced late-stage illness
< 6 mo life expectancy
Prior to methylnaltrexone
• < 3 BM/week or no BM for > 2 days
• After methylnaltrexone
• Slightly higher rate of elimination than placebo
• 4hr post dose BM
• 62% 0.15mg/kg; 58% 0.3 mg/kg, 15% placebo
• Not studied in pediatrics
Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness.
NEJM 2008;358(22):2332-43.
22/90
methylnaltrexone
Safety
ADRs
Precautions
•
•
•
•
•
•
Abdominal pain (29 vs 10%)
Flatulence (13 vs 6%)
Nausea (12 vs 5%)
Dizziness (7 vs 2%)
Diarrhea (6 vs 2%)
DIs
• Weak in vitro CYP2D6
inhibitor
• No effect in vivo on
dextromethorphan
metabolism (CYP2D6)
•
•
•
CI’d in mechanical GI
obstructions
Discontinue in severe diarrhea,
nausea, or abdominal pain
½ dose in severe renal
impairment (CrCl < 30mL/min)
Hepatic impairment
• No dose adjustment in mildmoderate
• Not studied in severe
•
•
•
Pregnancy Category B
S&E not established in peds
No dosage adjustment in elderly
23/90
methylnaltrexone
Administration
Storage & Prep
• 12mg/0.6mL single-use vial
• Store at RT, don’t freeze
Administration
• SC every other day prn
• Abdomen, thigh, upper arm
• Patient administered
Dosing
• Pts 38-61kg: 8mg (0.4ml)
• Pts 62-114 kg: 12mg (0.6ml)
• 0.15 mg/kg outside this range
at nearest 0.1ml (rounded up)
• CrCl <30mL/min: reduce by
50%
•
•
•
•
•
No more than one dose in a 24
hour period
Median time to laxation 30 min
Usually works w/in 4 hrs
Advise pts to be within close
proximity of toilet facility
Treatment doesn’t decrease
analgesic effect or precipitate
withdrawal
24/90
methylnaltrexone
• BMs, severe/persistent diarrhea, abdominal pain, renal
function
• Notes:
• Pts starting chronic opioids should also be on:
• stool softener (i.e. docusate)
• AND stimulant laxative (i.e. senna or bisacodyl)
• PO peripherally-acting opioid antagonist approved
• alvimopan (Entereg®)
• management of post-op ileus
• Increased CV risks delayed approval for opioid-induced
constipation in palliative care.
• CV risks have not been seen with methylnaltrexone.
• 12mg vial $50 retail
• Under investigation in decreasing incidence of opioid
N/V and preventing post-operative ileus
25/90
Gastroenterology
New Indications 2008
• natalizumab (Tysabri®)
• Previously approved for multiple sclerosis
• Approved 1/14/2008 for induction and maintenance
treatment of moderate to severe Crohn’s disease (CD)
refractory to other therapies.
• Prescribing, dispensing, and administration is limited to
the TOUCH program.
• Dose in CD is 300 mg IV over 1 hr every 4 weeks
• palonosetron (Aloxi®)
• Previously approved for prevention of CINV.
• Approved 3/2/2008 for the prevention of postoperative
N/V for up to 24 hrs following surgery.
Drug Information Online. www.drugs.com.
26/90
Neurology
Neurology
Partial Onset Seizures
27/90
Neurology – Partial Onset Seizures
Approved 10/28/2008
lacosamide
Vimpat®
• Oral: adjunctive therapy of partial onset seizures
• pts > 17 yo
• 50 mg BID, increased based on clinical response by 100mg/day
weekly up to 400mg/day
• ADR’s: vertigo, diplopia, NVD, fatigue, gait disturbance, HA,
dizziness, pruritus
• IV: short term replacement when PO is not feasible
•
•
•
•
•
over 30-60 minutes diluted or undiluted
IV daily dose equivalent to oral daily dose
200ml/20mL single-use vial; store at RT
Compatible w/ NSS, D5W & LR x24h in PVC or glass at RT
Additional ADR’s: injection site pain, irritation, erythema
Vimpat® (lacosamide) [package insert]. Smyrna GA: UCB, Inc. October 2008.
www.ClinicalTrials.gov
28/90
Neurology – Partial Onset Seizures
lacosamide
Administration
• Max dose 300mg/day in severe renal impairment
(CrCl<30mL/min) and mild/moderate hepatic
impairment
• Precautions: suicidal behavior & ideation,
dizziness, PR interval prolongation, abnormal
LFT’s
• Withdraw gradually over at least 1 week
• Pregnancy category C (registry), caution in Elderly
(small trial population)
• Under investigation for painful diabetic neuropathy,
chronic refractory neuropathic pain, migraine,
fibromyalgia
Vimpat® (lacosamide) [package insert]. Smyrna GA: UCB, Inc. October 2008.
29/90
Neurology
• IGIV (Gamunex®)
• Previously approved for Primary immunodeficiency
(PI) and idiopathic thrombocytopenic purpura (ITP)
• Approved 9/12/2008 for chronic inflammatory
demyelinating polyneuropathy (CIDP)
• Only IGIV FDA-approved for any neurological
disorder
• 2 Gm/kg loading dose; 1 Gm/kg maintenance dose
• Initial infusion rate: 2 mg/kg/min (2x PI & ITP rates)
• Maintenance infusion rate (if tolerated): 8 mg/kg/min
every 3 weeks.
Gammunex® (Human Immune Globulin Intravenous) [package insert]. Research Triangle Park NC: Talecris
Biotherapeutics, September 2008.
FDA/CBER. 2008 Biological License Applications. www.fda.gov
30/90
Rheumatology-Immunology
CAPS
HAE
31/90
Cryopyrin-associated
Periodic Syndromes (CAPS)
• Extremely rare inherited condition (unknown
frequency)
• Autosomal dominant inheritance; M:F = 1:1
• Familial Cold Auto-Inflammatory Syndrome (FCAS);
• AKA familial cold urticaria (FCU)
• Symptoms after exposure to cold
• Onset usually < 6 mos; episodes last < 24 hrs.
• Muckle-Wells Syndrome (MWS)
• Manifests at birth or in early infancy
• 300 pts in US; 50% due to gene mutation
FDA News. February 27, 2008.
E-Medicine. www.emedicine.medscape.com.
32/90
Cryopyrin-associated
Periodic Syndromes (CAPS)
• Symptoms: acute febrile attacks with profuse sweating,
abdominal pain, arthritis, urticaria (extremities & face),
conjunctivitis, fatigue
• MWS complicated by progressive nerve deafness and multiorgan
amyloidosis
• Without amyloidosis, life expectancy in FCAS is normal
• Inflammatory response due to excess IL-1, suggested by
favorable anecdotal response to anakinra.
• Treatment options: colchicine, high-dose corticosteroids,
and now … rilonacept
• anakinra (Kineret®)
• canakinumab (ACZ885) in Phase III trial
33/90
Rheumatology-Immunology - CAPS
Approved 2/27/2008
rilonacept
SQ
Arcalyst TM
•
•
•
•
•
•
First treatment for CAPS
Orphan drug approval
Chinese hamster ovary cells
Formerly known as IL-1 Trap
Blocks IL-1
Improvement in joint pain, rash,
fever/chills, eye irritation/pain, fatigue
• Approved in adults and children > 12 yo
Arcalyst™ (rilonacept) [package insert]. Tarrytown NY: Regeneron Pharmaceuticals, Inc. July 2008.
34/90
rilonacept
Clinical Trial
• Approval based on one mfr trial
• 47 pts
• Daily diary assessment (0-10) of 5 CAPS s/s:
joint pain, rash, feeling of fever/chills, eye
redness/pain, fatigue
• Relief of symptoms noted within several days
35/90
rilonacept
Safety
ADR’s
Precautions
•
•
•
•
Injection site reactions (48 vs
13%
URI (26 vs 4%)
Increased total cholesterol,
HDL, LDL & TG’s. Consider
lipid-lowering therapy based
on CV risk & guidelines.
DI’s
•
•
Rilonacept may normalize
CYP450 enzymes which have
been suppressed by cytokines
during chronic inflammation.
Therapeutically monitor
CYP450 dependant drugs (i.e.
warfarin) at rilonacept start.
•
•
•
•
•
•
•
•
IL-1 blockade may interfere w/
immune response to infections
Do not start in patients with
active/chronic infection
Do not co-administer with TNF
antagonists
Rare hypersensitivity
Administer all recommended
vaccinations BEFORE initiation
of rilonacept.
Pregnancy Category C
S/E not established in peds < 12
yo
S/E similar in elderly & younger
No studies in renal or hepatic
impairment
36/90
rilonacept
Administration
Storage & Prep
Dosing
• 220mg/20mL
lyophilized powder
• Refrigerate, protect
from light
• Reconstitute w/ 2.3mL
SWI (not supplied from
manufacturer)
• Viscous clear solution
• Use w/in 3hrs
• Adults
• Loading dose: two 160
mg (1ml) SC injections
• Continue with 160mg
(1ml) SC weekly
• Pediatrics (12-17yo)
• Loading dose 4.4mg/kg
(max above)
• Continue with 2.2mg/kg
SC weekly
37/90
rilonacept
• s/s CAPS, s/s infection, lipid profile, CRP, SAA
• Notes:
• First dose under healthcare professional supervision
• Subsequent reconstitution & self-administration
• Provide all supplies needed for self-administration
• Under investigation in familial Mediterranean fever
(FMF), CKD-related anemia, atherosclerosis, juvenile
idiopathic arthritis, gout.
38/90
Immunology
Hereditary Angioedema (HAE)
• Rare and potentially life-threatening inherited disease
• Low or nonfunctioning plasma protein C1 inhibitor (C1INH)
• Leads to activation of complement pathway
• 6,000 – 10,000 pts in US
• HAE attacks
• Begin in adolescence
• Rapid swelling of hands, feet, limbs, face, GI tract,
airway (leading to asphyxiation)
• Occurs during stress, surgery, infection
• Mortality rate 20-30% (prior to effective therapy)
• Since HAE does not respond well to usual therapies
for angioedema, correct diagnosis is paramount
• Treatment: respiratory support, surgical care, anabolic
steroids and fresh frozen plasma … now purified C1
inhibitor
FDA News. October 10, 2008.
E-medicine. www.emedicine.medscape.com
Images: www.allabouthae.com
39/90
Approved 10/10/2008
Immunology - HAE
Human C1 Inhibitor
IV
CinryzeTM
• Prevention of HAE attacks in adults &
adolescents
• Derived from human plasma
• MOA: regulate activation of complement,
intrinsic coagulation pathway, and
fibrinolysis.
• Effective in most but not all HAE pts
• IV q3-4 days
Cinryze™ (C1 Inhibitor, human) [package insert]. New York NY: Lev Pharmaceuticals. October 2008.
40/90
Human C1 Inhibitor
Immunology - HAE
Clinical Trial
•
•
•
•
One RDBPC mult-center cross-over study
24 pts w/ history of at least 2 attacks/mo
Mean age 31.8 (range 9-73)
Two groups
• Drug x 12 wks followed by placebo x 12 wks
• Placebo x 12 wks followed by drug x 12 wks
•
•
•
•
•
Pts recorded angioedema symptoms
Mean # of attacks: 6.1 drug vs 12.7 placebo
Mean attack severity: 1.3 vs 1.9 (score 1-3)
Mean attack duration: 2.1 vs 3.4 days
Days of swelling: 10.1 vs 29.6
41/90
Human C1 Inhibitor
Immunology - HAE
Safety
ADR’s
Precautions
•
•
•
•
•
•
•
Mild/moderate
URI
Sinusitis
Rash
HA
•
•
•
DI’s
Hypersensitivity
Thrombotic events in off-label
high-dose use
Pooled human plasma may
contain infectious agents (i.e.
CJD)
S&E not established in
neonates, infants, children
• Clinical trial included 3
children: 9, 14, 16 yo
• No studies conducted
•
Clinical trial included
insufficient elderly to determine
different response
42/90
Human C1 Inhibitor
Immunology - HAE
Administration
Storage & Prep
Dosing
• 500 unit freeze-dried
powder for reconstitution
• Refrigerate
• Protect from light
• Reconstitute w/ 5ml SWI
(not provided) using
transfer needle
• Withdraw via filter needle
• Use w/in 3 hours
• 1000 units IV Q 3-4 days
• Rate: 1 mL/min
43/90
Immunology - HAE
Human C1 Inhibitor
• s/s hypersensitivity
• s/s thrombosis: new swelling/pain in limbs or
abdomen, now chest pain, SOB, loss of
sensation, altered consciousness/speech
• Notes
• Under investigation in endotoxemia
• Recombinant product in clinical trial
44/90
• adalimumab (Humira®)
• Previously approved for rheumatoid arthritis
and psoriatic arthritis
• Approved 2/22/2008 for juvenile idiopathic
arthritis (JIA) in > 4yo
• abatacept (Orencia®)
• Approved 4/8/2008 for juvenile idiopathic
arthritis (JIA) in > 6 yo as monotherapy of in
combination with methotrexate.
45/90
Endocrinology
Endocrinology
Growth Hormone Deficiency
46/90
Approved 1/23/2008
Endocrinology – GHD
somatropin
SQ
AccretropinTM
• Pediatric Indications
• Growth failure due to inadequate secretion of
growth hormone
• 0.18 to 0.3 mg/kg divided into equal daily doses
given 6-7 times weekly SC
• Short stature due to Turner Syndrome prior to
epiphyses closure
• 0.36 mg/kg divided into equal daily doses given 67 times weekly SC
• Yet another growth hormone product!
Accretropin™ (somatropin) [prescribing information]. Winnipeg Canada: Cangene Corporation. March 2007.
47/90
Hematology
Hematology
Hemophilia
ITP
CLL/NHL
48/90
Hematology - Hemophilia
Approved 5/9/2008
IV
r-Factor VIIa
NovoSeven® RT
• recombinant Factor VIIa
• Room temperature storage for up to 2 yrs
• Sucrose and l-methionine
• Original formulation 3 yrs at refrigeration
• No change in indications:
• Bleeding and prevention of surgical bleeding in hemophilia A or
B with antibodies that neutralized Factors VIII or IX
• Bleeding and prevention of surgical bleeding in congenital Factor
VII deficiency
• Prevention of surgical bleeding in acquired hemophilia
• ADR’s: fever bleeding, injection site reaction, joint
discomfort, headache, elevation/fall BP, nausea,
vomiting, pain, swelling, rash.
FDA News. May 9, 2008.
49/90
Hematology - Hemophilia
Approved 2/21/2008
r-antihemophilic factor
IV
Xyntha™
• Additional treatment option
• Plasma and albumin free
• Minimizing risk of infection
• Indicated for
• Control & prevention of bleeding in patients with
hemophilia A
• Surgical prophylaxis in patients with hemophilia A
• 2 of 89 patient developed factor VIII inhibitors
• Store refrigerated.
• RT storage ok for up to 3 months.
Xyntha™ (recombinant antihemophilic factor) [package insert]. Philadelphia PA: Wyeth Pharmaceuticals, 2008.
50/90
Hematology
Immune Thrombocytopenic Purpura
• Pathophysiology
• Immunological destruction of platelets with bone marrow inability
to compensate for loss
• Abnormal IgG binds to circulating platelets
• Prevalence
• 140,000
• Bruising & risk of life-threatening bleeding
•
•
•
•
Corticosteroids
IVIG, IV RhIG, rituximab
Cyclophosphamide, azathioprine, danazol
Splenectomy
FDA News. August 22, 2008.
51/90
Approved 8/22/2008
Hematology - ITP
romiplostim
SQ
NplateTM
• Fc-peptide fusion protein produced by
recombinant DNA in E.coli
• MOA: increases platelet production by binding
and activating the TPO receptor
• Bone marrow platelet stimulant, increasing
production via TPO receptor
• Chronic ITP refractory to corticosteroids,
immunoglobulins, or splenectomy
• Use only in pts at risk for bleeding
• Do not use to normalize platelet count
Nplate™ (romiplostim) [package insert]. Thousand Oaks CA: Amgen, Inc. August 2008.
52/90
romiplostim
Hematology - ITP
Clinical Trials
• Approval based on 2 randomized parallel trials
• 125 patients who had received one prior ITP
treatment
• Pts w/ spleen in one study, w/o in other
• 6 months of treatment
• Pts tx’d w/ romiplostim maintained higher
platelet counts than those on placebo
• Overall platelet response rate 88% nonsplenectomised on drug, 79% splenectomised
on drug, 14% non-spelenectomised on placebo
Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic
purpura: a double-blind randomised controlled trial. Lancet 2008; 371(9610):395.
53/90
romiplostim
Hematology - ITP
Safety
ADRs
Precautions
• arthralgia, dizziness,
insomnia, myalgia,
extremity pain, abdominal
pain, shoulder pain,
dyspepsia, paresthesia
•
DIs
•
• Ok to admin w/
corticosteroids, danazol,
azathioprine, IVIG.
•
• If platelet count >
D/C these
• No formal studies
50x109/L,
•
•
•
•
•
•
CI’d in MDS, risk of acute
leukemia
Fibrous deposits in bone
marrow
Possible platelet drop below
baseline with romiplostim d/c
Blood clots possible due to
excessive platelet increases
(registry)
D/C romiplostim or
breastfeeding
Adjust doses in geriatrics
cautiously
No studies in renal or hepatic
impairment
54/90
romiplostim
Hematology - ITP
Administration
Storage & Prep
Dosing
•
•
•
•
•
•
250 & 500 mcg single use vials
Lyophilized powder
Protect from light
Reconstitute
• 250 mcg vial w/ 0.72 mL SWI
• 500 mcg vial w/ 1.2 mL SWI
• Final Conc = 500 mcg/mL
•
•
•
•
Swirl (< 2min), do not shake
Use w/in 24 hrs of
reconstitution (RT or refrig)
Use syringe w/ 0.01 mL
graduations
Administration by healthcare
provider enrolled in program or
under enrolled prescriber’s
direction
•
•
•
•
Initial 1mcg/kg SC QWK
Weekly adjustments by
1mcg/kg to platelet count >
50x109/L
Clinical trail median dose 2
mcg/kg
If platelet count > 200x109/L x
2 wks, reduce by 1mcg/kg
If platelet count > 400x109/L,
don’t dose. Assess weekly.
Resume when platelet count <
200x109/L
Max 10 mcg/kg
• D/C if platelets don’t increase
after 4 weeks on max dose
•
Do NOT use to normalize
platelet count
55/90
Hematology - ITP
romiplostim
• CBC/platelets baseline & weekly until dose
stabilized, then monthly, also x 2 wks after
D/C
• Notes
• FDA-mandated REMS to address risks
• Restricted distribution program
• Medication Guide
• Prescriber and patient enrollment
• Under investigation in MDS,
thrombocytopenia, lymphoma, pediatric ITP
56/90
Hematology
CLL
NHL
• Chronic Lymphocytic
Leukemia
• Progressive accumulation
of functionally
incompetent lymphocytes
• Most common form of
leukemia
• 17,000 new cases/yr
• Majority of pts live 5-10
yrs
• Majority of cases > 55yo
• Treatment options:
nucleoside analogues,
monoclonal antibodies,
allogeneic stem cell
transplantation
• Non-Hodgkin Lymphoma
• Tumors originating from
lymphoid tissue
• Progressive clonal
expansion of B cells (85%),
T cells and/or NK cells
• Est. 63,000 new cases of
NHL in 2007
• Incidence doubled since
1970’s (early detection?)
• 5-year survival 63%
• Improved survival over last
20 yrs
• Treatment options:
combination chemotherapy
57/90
Approved 3/20/2008
Hematology – CLL & NHL
bendamustine
IV
Treanda®
• Novel DNA-alkylating agent
• Used in EU for lymphoma for yrs
• FDA approved
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin lymphoma (NHL) that has
progressed in 6 months of treatment with a
rituximab regimen (10/31/2008)
FDA Press Release. March 20, 2008.
Treanda® (bendamustine) [package insert]. Frazer PA: Cephalon, Inc. 2008.
58/90
bendamustine
Clinical Trials
• Approval in CLL due to one unpublished study
• 305 pts previously untreated for CLL
• IV bendamustine vs PO chlorambucil (Leukeran®)
• chlorambucil not the best comparitor
• fludarabine (Fludara®) more effective
• fludarabine + rituximab (Rituxan®) +/- cyclophosphamide CLL
ORR 90%; CR 70%
CLL
bendamustine
chlorambucil
Overall response rate (ORR)
68%
39%
Complete response (CR)
30%
24%
Median progression-free survival
21.7 mo
9.3 mo
Median duration of remission
18.9 mo
6.1 mo
FDA Press Release. March 20, 2008. .
59/90
bendamustine
Clinical Trials
• Unpublished study
• 31 pts w/ relapsed CLL
• bendamustine + rituximab: ORR 65%; CR 13%
• Approval in progressed NHL w/in 6 mos of
treatment w/ rituximab regimen
• ORR >70% follicular, low-grade transformed NHL
refractory to rituximab regimens
• ORR 92% relapsed follicular, low-grade, and mantle
cell NHL.
60/90
bendamustine
Safety
ADR’s
• grade 3/4 neutropenia
(43%)
• grade 3/4 thrombocytopenia
(11%)
• nausea & vomiting (20%,
grade 3/4 <1%)
• fever, fatigue
DI’s
• increased concentrations of
bendamustine with CYP1A2
inhibitors (i.e. fluvoxamine,
ciprofloxacin)
• Decreased concentrations
of bendamustine with
CYP1A2 inducers (i.e.
carbamazepine, tobacco)
Precautions
•
•
•
•
•
•
•
•
•
•
•
CI’d in hypersensitivity to bendamustine
or mannitol
Potential concern: secondary
malignancies
Myelosuppression
Skin reactions: rash, toxic skin
reactions, bullous exanthema
Infectious deaths (3 pts w/ NHL),
myelodysplastic sydrome,
myelomonocytic leukemia
Infusion syndrome: fevers, hypotension,
chills, rigors, myalgias
Fatigue
Tumor lysis syndrome
Pregnancy Category D
No differences between geriatrics and
younger adults
61/90
bendamustine
Administration
Storage & Prep
• 100mg lyophilized
powder stored at RT
• Chemo precautions
• Reconstitute w/ 20mL
SWI
• Shake well
• Add to 500ml NSS w/in
30 min of reconstitution
• Final conc 0.2-0.6 mg/mL
• Stable 3h at RT, 24hrs
refrig
Dosing
•
CLL
• 100 mg/m2 IV over 30 min on
days 1 and 2 in 28 day cycle,
up to 6 cycles
•
NHL
• 120 mg/m2 IV over 60 min on
days 1 and 1 in a 21-day
cycle, for up to 8 cycles
•
•
•
Dosing adjustments for
hematologic toxicity
Moderate-severe hepatic
dysfunction: do not use
Renal dysfunction: do not use
if CrCl < 40 mL/min
62/90
bendamustine
• CBC, platelets
• Notes
• Consider using allopurinol in patients at high risk of
tumor lysis syndrome
• 100mg vial cost $2160 (Red Book AWP)
• Effective for CLL, but comparisons with other agents
are lacking
• Additional treatment option for NHL
• Under investigation in acute myeloid leukemia (AML),
myelodysplastic syndrome (MDS), acute lymphoblastic leukemia
(ALL), chronic myeloid leukemia (AML), metastatic breast
cancer, brain and CNS tumors, recurrent small cell lung cancer,
follicular lymphoma, sarcoma
63/90
Approved 12/15/2008
Hematology
plerixafor
SQ
Mozobil TM
• Hematopoietic stem cell mobilizer
• Used in combination with G-CSF to mobilized stem cells
for collection and autologous transplantation in patients
with NHL and MM
• Initiate after pt receives G-CSF qd x 4days (AM)
• Dose 0.25 mg/kg ABW SC 11 hrs (PM) prior to each
apheresis session
• Renal impairment (CrCl < 50 mL/min) decrease dose to
0.16 mg/kg
• ADRs: NVD, fatigue, injection site reaction, HA,
arthralgia, dizziness
• Potential for cell mobilization in leukemia patients
• Pregnancy Category D
• Store at room temperature
Mozobil™ (plerixafor) [package insert]. Cambridge MA: Genzyme Corporation. 2008.
64/90
Oncology
Oncology
Prostate Cancer
Chemotherapy-induced N/V
MTX rescue
65/90
Oncology
Prostate Cancer
• One of the most commonly diagnosed
cancers in the US
• Second leading cause of cancer death in
US men
• 2004: 190,000 diagnosed; 29,000 died
• Treatment options: Observation,
prostatectomy, radiation therapy
chemotherapy, hormone therapy
FDA News. December 29, 2008.
66/90
Approved 12/29/2008
Oncology – Prostate Cancer
degarelix
SQ
(Brand Name TBA)
• Gonadotropin releasing hormone (GnRH)
receptor inhibitor
• Slows growth & progression of prostate
cancer by suppressing testosterone
• Indicated for treatment of pts w/ advanced
prostate cancer
Degarelix [package insert]. Parsippany NJ: Ferring Pharmaceuticals. 2008.
NOTE: degarelix is the generic name.
67/90
degarelix
Clinical Trial
• degarelix vs leuprolide
• degarelix did not cause temporary
increase in testosterone
• Both drugs suppressed testosterone to
levels seen with orchiectomy
• Rates:
• degarelix 240/160mg: 98.3%
• degarelix 240/80mg: 97.2%
• leuprolide 7.5mg: 96.4%
Klotz L, Boccon-Gibod L. Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative,
randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int 2008; 102(11):1531-8.
68/90
degarelix
Safety
ADRs
• injection site reactions
(pain, redness,
swelling)
• hot flashes
• increased weight
• Fatigue
• LFT increases
DIs:
• Not studied
Precautions
• Long-term androgen
deprivation prolongs
QT interval
• Pregnancy Category
X
• S&E not established
for peds
• 82% trial pts > 65yo
• Not studied in renal or
hepatic impairment
69/90
degarelix
Administration
Storage & Prep
• 80 & 120mg vials
• Reconstitute w/ SWI
• 120mg – 3mL
• 80 mg – 4.2mL
• Keep vial vertical & swirl
gently (15 min)
• Do not turn vial upside
down to withdraw
• Do not shake
• Use w/in 1 hr
Dosing
• Initial: 240mg as
2x120mg deep SC
injections
• Maintenance: 80mg
deep SC q 28 days
• Abdominal area that will
not be exposed to
pressure
Under investigation in …
• Female infertility
• BPH
70/90
Approved 1/25/2008
Oncology - CINV
IV
fosaprepitant
Emend®
•
Prodrug of aprepitant, rapidly converts when given IV
• Selective antagonist of substance P
•
•
•
Indicated, in combo with other antiemetics for prevention of
acute & delayed NV associated with high and moderate
emetogenic chemotherapy
115 mg IV over 15 min can be substituted for 125mg PO aprepitant
30 min prior to chemo, on Day 1 only.
Aprepitant is mild CYP3A4 inhibitor. Do not use with pimozide,
terfenadine, astemizole, cisapride. Caution with ketoconazole, itraconazole,
nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir, diltiazem.
•
•
Administration of aprepitant with warfarin results in clinically
decreased INR.
Chronic use for NV not recommended.
Emend® (fosaprepitant) [prescribing information]. Whitehouse Station NJ: Merck & Co. January 2008.
71/90
Approved 3/72008
Oncology – MTX Rescue
levoleucovorin
IV
FusilevTM
• Pharmacologically active enantiomer of
leucovorin
• Indicated after high-dose MTX in osteosarcoma
or inadvertent FA antagonist overdose
• 50mg freeze-dried powder (w/ mannitol)
• Reconstitute w/ 5.3 mL 0.9% NSS = 10mg/mL
• Infuse nmt 160mg/min because of Ca content
•
•
•
•
½ usual dose of racemic form
Not studied in > 65 yo
Monitor sCr & MTX levels
Fusilev™ (levoleucovorin) [package insert]. Irvine CA: Spectrum Pharmaceuticals. 2008.
72/90
Oncology
• bevacizumab (Avastin®)
• previously approved for combination treatment metastatic colon
cancer
• Approved 2/22/2008 in combination with paclitaxel as first-line
treatment of HER2-negative metastatic breast cancer.
• pemetrexed (Alimta®)
• Approved in 2004 in combination with cisplatin for malignant
pleural mesothelioma and second-line treatment for metastatic
non-small cell lung cancer
• Approved 9/29/2008 in combination with cisplatin as first-line
treatment of metastatic nonsquamous non-small cell lung cancer
• imatinib (Gleevec®)
• Approved 12/22/2008 to slow the recurrence of post-surgery
aggressive gastrointestinal stromal tumors.
73/90
Dermatology
Dermatology
New Indication
74/90
Dermatology
• adalimumab (Humira®)
• Previously approved for rheumatoid arthritis
and psoriatic arthritis
• Approved 1/18/2008 for moderate to severe
chronic plaque psoriasis
75/90
Infectious Disease
Infectious Disease
Vaccines
76/90
Infectious Disease - Immunizations
Centers for Disease Control and Prevention. www.cdc.gov/vaccines
77/90
Infectious Disease - Immunizations
New Vaccines for Babies
•
Rotavirus Vaccine (Rotarix®)
•
•
•
•
Oral, live-attenuated monovalet
3rd approved, 2nd available
Prevent severe gastroenteritis in infants & children
Rotavirus causes 60,000 hospitalizations and 37
deaths in US annually
• Requires one less dose than other vaccine, but
includes only one serotype.
•
DTP-Polio (Kinrix™)
• Vaccine against diphtheria, tetanus, pertussis, and
poliomyelitis
• Similar protection to separate DTaP and IPV
• Protection against four diseases with one less shot
•
DTP-Polio-H.influenzae (Pentacel®)
• Vaccine against diphtheria, tetanus, pertussis,
poliomyelitis, and Haemophilus influenza
• Given as a four-dose series, reducing number of
shots by seven
Press Releases. June 23, 2008 and June 24, 2008.
78/90
Infectious Disease
• micafungin (Mycamine®)
• Previously approved for esophageal candidiasis and prophylaxis
of candida infections in BCT.
• Approved 1/23/2008 for disseminated candidiasis and candidemia
• human papilloma virus vaccine (Gardasil®)
• Approved in 2006 for prevention of cervical cancer caused by
HPV types 16 and 18
• Approved 9/12/2008 for the prevention of vaginal and vulvar
cancer caused by HPV types 16 and 18
• pegylated interferon & ribavirin (PegIntron® & Rebetol®)
• Approved 12/12/2008 for use in chronic hepatitis C in > 3yo
• Tdap (Boostrix®)
• Approved 12/4/2008 as a booster in adults
79/90
Pipeline Trends
80/90
FDA Drug Approval Process
• Drug application took longer to review during Q3
2008
• FDA focused on imaging agents
• EU focused on chronic conditions and general uses
• FDA missed deadlines on 20% of the159 new drug
application through 10/31/2008.
• FDA Hires
• 800 employees in 2008, training has taken time
• FDA plans to meet a 90% of its review deadlines in
2009 with the new hires
ASHP Daily Briefings. December 11, 2008. December 22, 2008.
81/90
• 21 new entities approved by FDA in 2008
• Up from 18 in 2007
• missed target review dates for at least 15 drugs
• staff given permission to miss review dates due to
personnel shortages
• Goal of reviewing 90% application on time will not be
met in 2008
• Drug review duration
• Standard: 10 months
• Priority: 6 months
ASHP Daily Briefings. December 11, 2008. December 22, 2008.
82/90
• Approval time trends
•
•
•
•
2006: 13.7 months
2005: 24 months
2004: 24.7 months
Priority drugs: 6 months (2004-2006)
• New drug development trends
• Personalized & specialized drugs
• Plan for unique and expensive therapies for
small populations
• Increase in orphan drug approvals
Hoffman JM, Shah ND, Vermeulen LC, et al. Projecting future drug expenditures 2009. AJHP 2009: 66:237-57.
83/90
Pipeline Driven by Biologics
• Historical development of small molecules
• 60% of revenue growth from biologicals is
forecast by non-biotech companies
• Prospective competition by bio-similars
• Monoclonal antibodies will be the stronger driver
for growth
• By 2010, annual sales of biologicals will have
increased by $26 billion, while small molecules
will have increased by $13 billion.
Pharmaceutical Business Review. Biologics driving growth to 2010. June 22, 2006.
84/90
Financial Impact
• Increased OOP burden on consumers
• Average 2007 co-payments
•
•
•
•
$10 – generics
$26 – preferred drugs
$46 – non-preferred drugs
$75 – fourth tier drugs
• high-cost drugs and biologicals
• Limited impact on drug expenditure for hospitals
& clinics
• Narrow application of new products
• Know hospital population!
85/90
2009 Parenteral Drug Pipeline
Neurology
• Fingolimod (FTY720, PO), alemtuzumab (Campath®), and
rituximab (Rituxan®) are in late-phase clinical trail for multiple
sclerosis.
• Dirucotide (MBP8298), an IV treatment, is in Phase III clinical trial
for secondary progressive multiple sclerosis.
Endocrinology
• Denosumab (AMG162, NDA 12/20/08) for osteoporosis. (Q4-2009)
Hematology
• Ferumoxytol (FerahemeTM, NDA 2/19/08) approval is delayed.
FDA requests additional non-trial information for this IV iron
treatment for CKD-related iron deficiency anemia
• Ecallantide (DX-88, BLA 11/21/2008) for hereditary angioedema
(HAE) granted FDA priority review 11/21/2008.
ASHP Daily Briefings (published daily).
86/90
Oncology
• Casopitant (Rezonic™) for CINV (Q-3 2009)
• Glucarpidase (Voraxaze™) for MTX toxicity (Q42009)
Dermatology
• Ustekinumab (CNTO1275, BLA 2/4/08) for
psoriasis. Approval declined 12/20. FDA wants
more information on mfr’s plan to inform physicians
and patients of potential risks. FDA advisory panel
unanimously recommended approval in June. (Q12009)
87/90
Infectious Disease
• Dalbavancin (Zeven®) for resistant Gm(+) infections now
pushed back to 2010 due to FDA request for Phase III noninferiority trial.
• Telavancin (TD-6424, Arbelic™, NDA 12/06) once-daily for
skin and skin structure infections (Q1-2009)
• Ceftobiprole (BAL5788, Zeftera™, NDA 5/18/07), a new
injectable anti-MRSA cephalosporin for skin and skin structure
infections, did not receive FDA approval due to concerns
about a few sites used in its study. This could delay US
approval into 2010. Approved in Canada in 2008. (Q2-2009)
• Motavizumab (Numax®, BLA 1/30/08) for RSV prevention did
not receive FDA approval. FDA requests more information.
(Q4-2009)
88/90
New Drug Approvals 2009
• Milnacipran (Savella™) approved 1/14/2009 for
fibromyalgia. (po)
• Human Fibrinogen Concentrate (RiaSTAP™)
approved 1/16/2009 for Congenital Fibrinogen
Deficiency.
• Antithrombin recombinant (ATryn®) approved
2/6/2009 for Antithrombin III Deficiency. First
transgenic therapeutic protein produced by
goats.
Stay tuned for
‘New Drugs VIII’ in 2010!
89/90
Questions?
annanv@anovation.us
90/90

New Parenteral Drugs and Biologicals 2008 NHIA Annual Conference

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