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

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“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.

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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.

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Pulmonology

Pulmonology PAH News

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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.

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Cardiology

Cardiology Severe Hypertension

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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.

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Gastroenterology

Gastroenterology Crohn’s Disease Opioid Constipation

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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.

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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 Pharmacist's Letter/Prescriber's Letter 2008;24(6):240607. FDA News. April 22, 2008. E-Medicine. www.emedicine.medscape.com. July 18, 2007.

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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 Pharmacist's Letter/Prescriber's Letter 2008;24(6):240607. FDA News, April 22, 2008. The Medical Letter 2008; 60(1297):81-2. Cimzia® (certolizumab pegol) [package insert]. Smyrna GA: UCB, Inc. April 2008.

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Gastroenterology – Crohn’s Disease

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.

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Gastroenterology – Crohn’s Disease

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 4 mo not studied • Not a controlled substance Pharmacist's Letter/Prescriber's Letter 2008;24(6):240608. FDA News. April 24, 2008. The Medical Letter 2008;50(1292):63. Resistor® (methylnaltrexone) [package insert]. Philadelphia PA and Tarrytown NY: Wyeth Pharmaceuticals and Progenics Pharmaceuticals; April 2008.

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Gastroenterology – Opioid Constipation

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 FDA News. April 24, 2008. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. NEJM 2008;358(22):2332-43.

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methylnaltrexone

Gastroenterology – Opioid Constipation

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

Pharmacist's Letter/Prescriber's Letter 2008;24(6):240608. FDA News. April 24, 2008. Resistor® (methylnaltrexone) [package insert]. Philadelphia PA and Tarrytown NY: Wyeth Pharmaceuticals and Progenics Pharmaceuticals; April 2008.

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methylnaltrexone

Gastroenterology – Opioid Constipation

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 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

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Neurology – Partial Onset Seizures

lacosamide

Administration • Max dose 300mg/day in severe renal impairment (CrCl 12 yo FDA News. February 27, 2008. E-Medicine. www.emedicine.medscape.com. Arcalyst™ (rilonacept) [package insert]. Tarrytown NY: Regeneron Pharmaceuticals, Inc. July 2008.

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Rheumatology-Immunology - CAPS

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

FDA News. February 27, 2008.

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Rheumatology-Immunology - CAPS

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

FDA News. February 27, 2008. Arcalyst™ (rilonacept) [package insert]. Tarrytown NY: Regeneron Pharmaceuticals, Inc. July 2008.

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Rheumatology-Immunology - CAPS

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

FDA News. February 27, 2008. Arcalyst™ (rilonacept) [package insert]. Tarrytown NY: Regeneron Pharmaceuticals, Inc. July 2008.

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Rheumatology-Immunology - CAPS

rilonacept

Care Plan Highlights • Assess & Monitor • 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. Arcalyst™ (rilonacept) [package insert]. Tarrytown NY: Regeneron Pharmaceuticals, Inc. July 2008. www.ClinicalTrials.gov

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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

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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 FDA News. October 10, 2008. Cinryze™ (C1 Inhibitor, human) [package insert]. New York NY: Lev Pharmaceuticals. October 2008.

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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

Cinryze™ (C1 Inhibitor, human) [package insert]. New York NY: Lev Pharmaceuticals. October 2008.

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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) Pregnancy Category C 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

FDA News. October 10, 2008. Cinryze™ (C1 Inhibitor, human) [package insert]. New York NY: Lev Pharmaceuticals. October 2008.

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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

Cinryze™ (C1 Inhibitor, human) [package insert]. New York NY: Lev Pharmaceuticals. October 2008.

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Immunology - HAE

Human C1 Inhibitor

Care Plan Highlights • Assess & Monitor • 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 Cinryze™ (C1 Inhibitor, human) [package insert]. New York NY: Lev Pharmaceuticals. October 2008. www.ClinicalTrials.gov

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Rheumatology-Immunology

New Indications 2008 • 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. Drug Information Online. www.drugs.com.

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Endocrinology

Endocrinology Growth Hormone Deficiency

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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! Drug Information Online. www.drugs.com. Accretropin™ (somatropin) [prescribing information]. Winnipeg Canada: Cangene Corporation. March 2007.

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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. FDA/CBER. 2008 Biological License Applications. www.fda.gov

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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. Drug Information Online. www.drugs.com.

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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

• Morbidity & Mortality • Bruising & risk of life-threatening bleeding

• Treatment Options • • • •

Corticosteroids IVIG, IV RhIG, rituximab Cyclophosphamide, azathioprine, danazol Splenectomy

FDA News. August 22, 2008. E-medicine. www.emedicine.medscape.com

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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 FDA News. August 22, 2008. Nplate™ (romiplostim) [package insert]. Thousand Oaks CA: Amgen, Inc. August 2008.

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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 FDA News. August 22, 2008. 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.

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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 Pregnancy Category C (registry) D/C romiplostim or breastfeeding S&E not established in peds Adjust doses in geriatrics cautiously No studies in renal or hepatic impairment

FDA News. August 22, 2008. Nplate™ (romiplostim) [package insert]. Thousand Oaks CA: Amgen, Inc. August 2008.

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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

Nplate™ (romiplostim) [package insert]. Thousand Oaks CA: Amgen, Inc. August 2008.

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Hematology - ITP

romiplostim

Care Plan Highlights • Assess & Monitor • 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 Nplate™ (romiplostim) [package insert]. Thousand Oaks CA: Amgen, Inc. August 2008. www.ClinicalTrials.gov

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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

E-medicine. www.emedicine.medscape.com

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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)

The Medical Letter 2008;50(1299):91. FDA Press Release. March 20, 2008. Treanda® (bendamustine) [package insert]. Frazer PA: Cephalon, Inc. 2008.

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bendamustine

Hematology – CLL & NHL

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

The Medical Letter 2008;50(1299):91. FDA Press Release. March 20, 2008. .

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Hematology – CLL & NHL

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.

The Medical Letter 2008;50(1299):91.

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bendamustine

Hematology – CLL & NHL

Safety ADR’s • grade 3/4 neutropenia (43%) • grade 3/4 thrombocytopenia (11%) • nausea & vomiting (20%, grade 3/4 65yo • Not studied in renal or hepatic impairment

FDA News. December 29, 2008. Degarelix [package insert]. Parsippany NJ: Ferring Pharmaceuticals. 2008.

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degarelix

Oncology – Prostate Cancer

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

Degarelix [package insert]. Parsippany NJ: Ferring Pharmaceuticals. 2008. www.ClinicalTrials.gov

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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.

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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 Pregnancy Category C Not studied in > 65 yo Monitor sCr & MTX levels

Drug Information Online. www.drugs.com Fusilev™ (levoleucovorin) [package insert]. Irvine CA: Spectrum Pharmaceuticals. 2008.

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Oncology

New Indications 2008 • 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. Drug Information Online. www.drugs.com The Medical Letter 2008;50(1285):34.

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Dermatology

Dermatology New Indication

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Dermatology

New Indications 2008 • adalimumab (Humira®) • Previously approved for rheumatoid arthritis and psoriatic arthritis • Approved 1/18/2008 for moderate to severe chronic plaque psoriasis

Drug Information Online. www.drugs.com

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Infectious Disease

Infectious Disease Vaccines

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Infectious Disease - Immunizations

Centers for Disease Control and Prevention. www.cdc.gov/vaccines

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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

The Medical Letter 2008;50(1293):66. FDA News. April 3, 2008. Press Releases. June 23, 2008 and June 24, 2008.

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Infectious Disease

New Indications 2008 • 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 Drug Information Online. www.drugs.com FDA/CBER. 2008 Biological License Applications. www.fda.gov

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Pipeline Trends

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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.

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FDA Drug Approval Process • 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.

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FDA Drug Approval Process • 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.

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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.

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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! Hoffman JM, Shah ND, Vermeulen LC, et al. Projecting future drug expenditures 2009. AJHP 2009: 66:237-57.

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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. Hoffman JM, Shah ND, Vermeulen LC, et al. Projecting future drug expenditures 2009. AJHP 2009: 66:237-57. ASHP Daily Briefings (published daily). Drug Information Online. www.drugs.com. www.ClinicalTrials.gov

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2009 Parenteral Drug Pipeline 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) Hoffman JM, Shah ND, Vermeulen LC, et al. Projecting future drug expenditures 2009. AJHP 2009: 66:237-57. ASHP Daily Briefings (published daily). Drug Information Online. www.drugs.com. www.ClinicalTrials.gov

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2009 Parenteral Drug Pipeline 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) Hoffman JM, Shah ND, Vermeulen LC, et al. Projecting future drug expenditures 2009. AJHP 2009: 66:237-57. ASHP Daily Briefings (published daily). Drug Information Online. www.drugs.com. www.ClinicalTrials.gov

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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! Drug Information Online. www.drugs.com.

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Questions? [email protected]

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