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Review of Novel Medication Use
in the NICU Population
Allison Jun, Pharm.D.Clinical Pharmacy Manager
Neonatal Clinical Pharmacist
Children’s Hospital of Orange County
Tina Lee, Pharm.D.Neonatal Clinical Pharmacist
Children’s Hospital of Orange County
Learning Objectives
•Understand selected disease states commonly seen in premature neonates
•Identify unique or unconventional indications for medications discussed
•Identify practical challenges associated with using these medication in the neonatal population
Overview•Review selected disease states in neonates
•Discuss therapy options for disease states
•Compare indications between adult population and neonatal population
•Typical Indications: Analgesia, osteoarthritis, inflammatory diseases, fever
•Mechanism of Action: Reversibly inhibits cyclooxygenase-1 and 2 enzymes, which results in decreased formation of prostaglandin precursors.
•Typical dosage forms: Tablets, capsules, suspension
Ibuprofen: Non-steroidal anti-inflammatory drug (NSAID)
Patent Ductus Arteriosus (PDA): Background•Ductus arteriosus is a bypass vessel that re-routes fetal circulation
•Fetus requires an open ductus arteriosus to allow blood to bypass pathway to lungs
•Once umbilical cord is cut, the neonate needs their lungs to supply oxygen
•The DA usually closes in response to increase in PO2 within the first 24 hours of life
http://www.npr.org/sections/health-shots/2013/08/30/216479305/money-may-be-motivating-doctors-to-do-more-c-sections
•Over-circulation to the lungs
•Clinical signs and symptoms develop:• Distinguishable murmur due to shunting of circulation• Bounding pulses with wide pulse pressure• Respiratory distress due to pulmonary edema, CHF• Poor feeding, necrotizing enterocolitis• Renal dysfunction from poor cardiac output• Metabolic acidosis• Poor weight gain
Patent Ductus Arteriosus: BackgroundIf PDA Persists…
•Prostaglandins (PGE2 and PGI2) play significant role in maintaining ductal patency
•COX inhibitors ideal target for therapy
•Mechanism of Action: Reversibly inhibits cyclooxygenase-1 and 2 enzymes, which results in decreased formation of prostaglandin precursors.
•Dosage forms used for PDA treatment: Injection – ibuprofen lysine
Treatment of PDA with Ibuprofen lysine
Efficacy:
•Equally efficacious as indomethacin•Closure rate 70% (ibuprofen) vs 66% (indomethacin)•Second course required 16% (ibuprofen) vs 12% (indomethacin)
Treatment of PDA with Ibuprofen lysine
Safety:
•Oliguria significantly reduced in patients receiving ibuprofen vs. indomethacin
•UOP significantly reduced in patients receiving indomethacin vs. indomethacin
•Increased SCr was significantly greater in patients receiving indomethacin vs. ibuprofen
•No differences in incidences of NEC, IVH or survival rate
Treatment of PDA with Ibuprofen lysine
•Infection
•Congenital heart disease requiring open ductus
•Active bleeding (IVH, GI)
•Thrombocytopenia
•Coagulation defects
•Necrotizing enterocolitis (NEC)
•Renal dysfunction
Ibuprofen lysine: Contraindications
•First line pharmacological treatment• Cost considerations
• Second course
•Alternative: Surgical ligation
•Practical Considerations: IV vs Oral dosage forms
Ibuprofen lysine: Place in therapy
PropranololBeta blocker
•Typical Indications: Management of hypertension; angina pectoris, supraventricular arrhythmias, ventricular tachycardias
•Mechanism of Action: beta-adrenergic blocker that competitively blocks response to beta adrenergic stimulation
•Typical dosage forms in adults: Tablets, capsules, injection
•Benign vascular tumors
•Most common tumor of childhood – 10% of all infants
•Underlying cause unknown
•Most frequent occurrence in females and premature infants
•Proliferate over first 2 – 3 weeks of age
•Most common location = head and neck
•Proliferative phase = 2 – 6 months
•Involutive phase = up to 10 years
Infantile Hemangioma (IH): Background
•Symptoms: Red lesion(s) – rapid growth in early weeks of life• “Strawberry mark”
• “Stork bite”
• Pain
• Bleeding
• Risk factors
• Caucasian
• Female
• Low birth weight
Infantile Hemangiomas: Background
•Accidentally discovered efficacy of propranolol in IH in 2008
•Propranolol initiated in patient with IH for cardiomyopathy
•Mechanism of action in IH unknown
•Possibly due to reduction in VEGF
•Typical dosage forms used: Oral liquid
Treatment of IH with propranolol
https://www.researchgate.net/figure/236225663_fig1_Possible-mechanisms-of-action-of-propranolol-in-infantile-hemangiomas-IHs-In-the
Treatment of IH with PropranololEfficacy
•Successfully treated IH at a rate of 60% vs placebo • 24 week treatment course
•Significant improvement by week 5 of treatment in 88% of IH patients
•Optimal dose = 3 mg/kg/day divided BID
N Engl J Med 2015;372:735-46.
Adverse effects reported infrequently include:
•Hypoglycemia
•Hypotension
•Bradycardia
•Bronchospasm
Propranolol Treatment Protocol
•Initiation in hospital
•Monitoring blood glucose, blood pressure, heart rate
Treatment of IH with PropranololSafety
•Hypoglycemia
•Hypotension
•Heart block
•Bradycardia
Treatment of IH with Propranolol: Contraindications
•First Line Pharmacological Treatment• New product introduced: Hemangeol®
•Alternatives: Steroids, Laser therapy
•Second line: Vincristine, Interferon
Treatment of IH with Propranolol: Place in Therapy
•Indications Metastic colorectal cancer
Non-squamous non-small cell lung cancer
Glioblastoma
Metastatic renal cell carcinoma
Cervical Cancer
•Mechanism of Action: antivascular endothelial growth factor (VEGF) monoclonal antibody
binds with isomers of VEGF receptors A and B
reduces the drive for angiogenesis and vascular permeability
•Typical dosage form: IV
Bevacizumab
Retinopathy of Prematurity (ROP)
• Retinopathy of Prematurity (ROP) is caused by abnormal retinal blood vessels in premature infants. ROP can resolve without any
damage to the retina
May be severe causing retinal detachment
Figure 1. Progression of retinopathy of prematurity (from Hallstrom, 2013)
•Risk FactorsOxygen
Gestational age and birthweight
Hyperglycemia, insulin, and nutrition
Neonatal infection
Retinopathy of Prematurity (ROP)
Retinopathy of Prematurity (ROP)
•Classification and screeningZone: I, II, III, IV
Stage: 1,2,3,4,5
Extent Described by dividing the retinal surface
into 30◦ sectors
Presence or absence of plus disease Plus disease is the presence of increased
dilation and tortuosity of retinal arterioles and venules in the posterior pole of the retina
Figure 2. Zones and Stages of ROP (from Hallstrom, 2013)
•ScreeningBirth weight <1500 gm or gestational age (GA) < 30 weeks
Birth weight between 1500-200 gm or GA >30 weeks whose clinical course places them at increase risk
•When to initiate treatment Zone 1 ROP: any stage with plus disease
Zone 1 ROP: stage 3- no plus disease
Zone 2 ROP: stage 2 or 3 with plus disease
Retinopathy of Prematurity (ROP)
•TreatmentCryotherapy Freezing the peripheral retina through the wall of the eye, including sclera
and chorioid
Photocoagulation – laser photocoagulationBecame gold standard for the treatment of ROP
Aimed through the pupil and focused on the avascular retina
Retinopathy of Prematurity (ROP)
Bevacizumab•Advantages over laser photocoagulation
Ease of administration
Rapid response because it binds to VEGF directly
Used in infants who cannot have laser photocoagulation
•Disadvantages
Long term systemic effects
Timing of administration
Minimum effective dose is not established
•Practical ConsiderationsCost
May take dose from oncology patients
Figure 3. Pathogenesis and therapy of ROP (from Mintz -Hittner 2011)
•MethodsProspective, controlled, randomized, stratified, multicenter trial to assess intravitreal bevacizumab
monotherapy for zone I or zone II posterior stage 3+ ROP
Randomized to bevacizumab (0.625 mg/0.02 ml) or conventional laser therapy
•Results150 infants: 143 survived to 54 weeks postmenstrual age, 7 infants died (not included in primary
outcome)
ROP recurred in 4 infants in the bevacizumab group (6 or 140 eyes) and 19 infants in the laser-therapy group (32 of 146 eyes), P=0.002
Significant treatment effect was found for Zone I ROP (P=0.003) but not for Zone II disease (P=0.27)
•ConclusionsIntravitreal bevacizumab monotherapy compared to laser therapy in infants with stage 3+ROP showed a
significant benefit for Zone I but not Zone II. Development of peripheral retinal vessels continued after treatment with bevacizumab, but laser therapy led to a permanent destruction of the peripheral retina
Efficacy of Intravitreal Bevacizumab for Stage 3+ ROP
•MethodsRetrospective analysis of data already collected as part of an observational cohort study form the Canadian
Neonatal Network (CNN) and the Canadian Neonatal Follow-Up Network (CNFUN)Infants born at <29 weeks in 2010-2011 with ROP Neurodevelopmental outcome at 18 month was assessed by using neurologic exam and Bayley Scales of Infant
and Toddler Developmental 3rd EdRegression analyses were performed
•Results125 treated infants: 27 treated with bevacizumab, 98 received laser Bevacizumab group obtained a median Bayley Scales of Infant and Toddler Development motor composite score
of 81 (interquartile range, 70-91). Laser group = 88 (interquartile range 79-97)Language score: bevacizumab = 79 (65-97). Laser = 89 (74-97)Cognitive score: bevacizumab = 90(80-100). Laser = 90 (85-100). Difference was detected in motor score only
(p=0.02)
•ConclusionsTreatment with bevacizumab vs laser had higher odds of severe neurodevelopmental disabilitiesFurther studies are needed
Neurodevelopmental Outcomes Following Bevacizumab Injections for ROP
•Indications • Respiratory infections • Listeriosis caused by Listeria monocytogenes• Pertussis caused by Bordetella pertussis • Skin and skin structure• Respiratory tract infections caused by Mycoplasma pneumoniae• Skin and skin structure (mild to moderate) caused by Streptococcus pyogenes or Staphylococcus aureus• Diphtheria: Infections due to Corynebacterium • Erythrasma: In the treatment of infections due to Corynebacterium minutissimum.• Intestinal amebiasis caused by Entamoeba histolytica (oral erythromycins only). • Extraenteric amebiasis requires treatment with other agents.• Acute pelvic inflammatory disease caused by Neisseria gonorrhoeae: • Syphilis caused by Treponema pallidum: as an alternate choice of treatment for primary syphilis in patients allergic
to the penicillins• For the treatment of the following infections caused by Chlamydia trachomatis: conjunctivitis of the newborn,
pneumonia of infancy, and urogenital infections during pregnancy.• Treatment of nongonococcal urethritis caused by Ureaplasma urealyticum.• Legionnaires' Disease caused by Legionella pneumophila . Although no controlled clinical efficacy studies have been
conducted, in vitro and limited preliminary clinical data suggest that erythromycin may be effective in treating Legionnaires' Disease.
Erythromycin
•Mechanism of Action: inhibits RNA-dependent protein synthesis at the chain elongation step; binds to the 50S ribosomal subunit resulting in blockage of transpeptidation
•Typical dosage form: capsules, tabs, suspension, IV
Erythromycin
•Gastric emptying and intestinal motilityGut immaturity During interdigestive periods, there are multi-phasic cycles of intestinal motor activity
termed migratory motor complex (MMC)
Physiologic studies show a lack of propagative phase III of the migratory motor complex in the duodenum of preterm infants <32 weeks gestational age
This immaturity predisposes them to feeding intolerance
Feeding Intolerance in Preterm Infants
•Growth restriction is a major and almost universal issue in pretermAchieving full feeds for optimizing enteral nutrition is very difficult due to GI
hypomotility and the risk of necrotizing enterocolitis (NEC)Long term TPN’s adverse reactions Line infections and sepsis
Cholestasis
Bone disease
•Signs and symptoms Gastric residualsEmesisAbdominal distentionVisible bowel loopsCharacter of stools: diarrhea, guaiac positive of bloody
Feeding Intolerance in Preterm Infants
Prevention and Treatment of Feeding Intolerance in Preterm Infants •Limited number of GI motility agents since cisapride was removed from the market
•Erythromycin Motilin, a GI peptide produced by the
enterochromaffin cells in the duodenal and jejuna mucosa and release periodically into the circulation in the fasted state
Causes contractions in the stomach and duodenum which extends distally along to the small intestine
Erythromycin has a high affinity for the motilin receptor Motility caused by direct activation of motilin receptors
Efficacy of Intermediate-Dose Oral Erythromycin on Very Low Birth Weight Infants with Feeding Intolerance
•Results from previous studies significantly vary due to different medications dosages, routes of administration and therapy durations
•Methods 45 VLBW infants with feeding intolerance who were at least 14 days old
Randomly allocated to a treatment group and administered 5 mg/kg oral erythromycin every 6 hours for 14 days (n=19)
Another set (n=26) were randomly assigned to the control group, which was not administered erythromycin
•Results The number of days to achieve full enteral feeing: 36.5±7.4 w/erythromycin vs 54.7 ±23.3 days control (p=0.01)
Duration of parenteral nutrition (p<0.05) and the time to reach body weight ≥ 2500g (p<0.05) were significant shorter in the erythromycin group
Incidence of parenteral nutrition associated cholestasis and necrotizing enterocolitis ≥ stage II after 14 days of treatment wassignificantly lower in the erythromycin group (p<0.05)
No significant difference were observed in terms of the incidences of sepsis, BPD, or ROP.
No adverse effects were associated with erythromycin treatment
•Conclusions Intermediate dose is effective and safe for the treatment of feeding intolerance is ELBW
•ConsiderationsTrial of intermediated dose of oral erythromycin at 5 mg/kg/dose PO Q8-6Hrs
after 14 days of life Low dose may not result in adequate serum concentrations to have prokinetic effects
Re-evaluate treatment after 14 days
PO route may be preferred IV route may be related to life threatening and fatal cardiac complications
Prevention and Treatment of Feeding Intolerance in Preterm Infants
•Indications:Mucolytic agent for such conditions as: Chronic bronchopulmonary disease: chronic emphysema, emphysema with bronchitis, chronic asthmatic bronchitis,
tuberculosis…etc)
Acute bronchopulmonary disease (PNA, bronchitis, tracheobronchitis)
Pulmonary complications of cystic fibrosis
Tracheostomy care
Pulmonary complications associated with surgery
Use during anesthesia
Post-traumatic chest conditions
Atelectasis due to mucous obstruction
Diagnostic bronchial studies
Antidote for acetaminophen toxicity
•Mechanism of ActionExerts mucolytic action by its free sulfhydryl group which opens up the disulfide bonds in the
mucoproteins thus lowering mucous viscosity
Acts as a hepatoprotective agent by restoring hepatic glutathione, serving as a glutathione substitute, and enhancing the nontoxic sulfate conjugation of acetaminophen
Acetylcysteine
•Multifactorial but mostly associated with the immaturity of the intestinal function and dysmotility25-27 weekers have a significant delay in their first stooling due to
physiologically immature motility of the intestines
Disorganized pattern of slow migrating intestinal motor complexes at 27-30 weeks
Increased viscosity of meconium Reduced water content of the stool can lead to meconium obstruction
Histological findings suggest increased viscosity of exocrine secretions
Meconium Obstruction in Prematurity Infant
Meconium Obstruction in Prematurity Infant•Risk FactorsMom Magnesium – affects smooth muscle, slowing down motility
Use of opiates
Diabetes – excess glucagon production which in turn decreases bowel motility
Pregnancy induce hypertension – leads to hypo-perfusion to intestine
Baby Sepsis – leads to intestinal dysfunction
Prone to develop RDS with associated delaying in gastric emptying
•Signs and Symptoms Usually presents at 10-14 days of life but conditions may
present any time after birth
Progressive abdominal distension in a baby who has previous passed smear of meconium, often after rectal stimulation, but failed to evacuate
Visible and palpable loops of bowel on abdominal exam
Plain films: show multiple dilated loops of bowel, without pneumatosis
•ComplicationsVery nonspecific
Difficulty in recognition, diagnosis and management Inherent dysfunction of many ELBW
Difficulty for clinicians to know if it is meconium obstruction due to non-specific signs and symptoms
No standardize management
•Management Rectal stimulation glycerine suppositories or saline irrigation
N-acetylcysteine
Contrast enema Diluted gastografin enema
Surgery
Meconium Obstruction in Prematurity Infant
•Rectal Irrigation Benefits best achieved if left for 30-50 mins Risk of colonic perforation
•Oral See some results in CF patientsUsing 10% solutions 1-5 ml PO Q6H Complications Hypernatremia
Hypovolemia
Mucosal ulceration
Acetylcysteine
1. Which of the following is a contraindication to using ibuprofen lysine for treatment of PDA?◦ A. Thrombocytopenia
◦ B. Necrotizing enterocolitis
◦ C. Renal dysfunction
◦ D. All of the above
Test Questions
1. Which of the following is a contraindication to using ibuprofen lysine for treatment of PDA?◦ A. Thrombocytopenia
◦ B. Necrotizing enterocolitis
◦ C. Renal dysfunction
◦ D. All of the above
Test Questions
2. Which pre-treatment assessment would be least appropriate for babies starting propranolol for IH?
◦ A. Blood glucose
◦ B. Renal function
◦ C. Heart rate
◦ D. Blood pressure
Test Questions
2. Which pre-treatment assessment would be least appropriate for babies starting propranolol for IH?
◦ A. Blood glucose
◦ B. Renal function
◦ C. Heart rate
◦ D. Blood pressure
Test Questions
3. Which one is NOT an advantage for using bevacizumab for retinopathy of prematurity.◦ A. Ease of administration
◦ B. Long term side effects are not well established
◦ C. Rapid response because it binds to VEGF directly
◦ D. Use in infants who cannot have laser photocoagulation
Test Questions
3. Which one is NOT an advantage for using bevacizumab for retinopathy of prematurity.◦ A. Ease of administration
◦ B. Long term side effects are not well established
◦ C. Rapid response because it binds to VEGF directly
◦ D. Use in infants who cannot have laser photocoagulation
Test Questions
•Neoprofen [package insert]. Charleston, SC: AAIPharma Services; 2013
• Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med; 2000;343:674-81.
•Heyman E, Morage I, Batash D, et al. Closure of patent ductus arteriosus with oral ibuprofen suspension in premature newborns: a pilot study. Pediatrics; 2003 Nov;112(5)e354.
•Cherif A, Khrouf N, Jabnoun S, et al. Randomized pilot study comparing oral ibuprofen with intravenous ibuprofen in very low birth weight infants with patent ductus arteriosus. Pediatrics; 2008 Dec;122(6)e1256-61.
•Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2015 Feb 18;(2).
•Leaute-Labreze C, Hoeger P, Mazereeuw-Hautier J, et al. A randomized, controlled trial of oral propranolol in infantile hemangioma. N Engl J Med: 2015; 372:735-46.
•De Graaf M, Breur JM, Raphael MF, et al. Adverse effects of propranolol when used in the treatment of hemangiomas: a case series of 28 infants. J Am Acad Dermatol. 2011 Aug;65(2):320-7.
References
•Avastin®[package insert]. San Francisco, CA: Genetech, Inc; 2015
•Mintz-Hittner HA, Kennedy KA, and Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med; 364(7):603-615
•Hellstrom A, Smith L EH, Dommann O. Retinopathy of prematurity. Lancet. 2013;382:1445-5
•American Academy of Pediatrics. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2013;131(1):189-195. http://pediatrics.aappublications.org/content/131/1/189#T1
•Morin, J, Luu, TM, Superstein R, et al. Neurodevelopmental outcomes following bevacizumab injections for retinopathy of prematurity. Pediatrics. 2016;137(4), April 2016:e20153218
•EryPed®[package insert]. North Chicago, IL:Abbott Laboratories
•Ng E, Shah VS. Erythromycin for the prevention and treatment of feeding intolerance in preterm infants. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD001815. DOI:10.1002/14651858.CD00185.pub2
•Curry JI, Lander TD, Stringer MD. Review artcle: erythromycin as a prokinetic agent in infants and children. Aliment Pharmacol Ther 2001;15:595-603
References
• Ng YY, Su PH, Chen JY, et al. Efficacy of intermediate-oral dose erythromycin on very low birth weight infants with feeding intolerance. Pediatr-neonatal 2012;53:34-40
•Patole S, Rao S, and Doherty d. Erythromycin as a prokinetic agent in preterm neonates: a systematic review. Arch. Dis. Child. Fetal Neonatal Ed. 2005;90:301-306
•Cooper WO, Griffin MR, Arbogast P, et al. Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis. Arch PediarAdolesc Med. 2002;156:647-650
•Siddiqui MF, Drewett M, and Burge DM. Meconium obstruction of prematurity. Arch Dis Child Fetal neonatal Ed. 202;97:F147-150
•EmilS, Nguyen T, Sills J, and Padilla G. meconium obstruction in extremely low-bith-weight neonates: guidelines for diagnosis and management. Journal of pediatric surgery. 2004;39(5)May:731-737
•Garza-Cox S, Keeney SE, Angel CA et al. Meconium obstruction in the very low birth weight premature infant. Pediatrics. 2004;114(1):285-290
References