DRUG THERAPY IN PREGNANCY, NEONATES, AND PEDIATRICS Amber Lucas, PharmD Saint Luke’s Hospital of Kansas City Causes of Infant Mortality Birth defects are the most common cause of infant mortality in countries with a low infant mortality rate Overall risk of 3% Cause for the majority of cases is unknown Environment (drug exposures) accounts for 3% What is a Teratogen? A substance, organism, or physical agent that is capable of causing abnormal development A teratogen can cause abnormalities of structure or function, growth retardation, or death of the organism. Classic teratogens – isotretinoin (Accutane®) or thalidomide GOALS Learn background for prescribing for pregnant and lactating patients. 2. Understand differences in prescribing for pediatric patients. 3. Learn current treatment recommendations for common pediatric illnesses. 4. Develop understanding for use of vaccines in pediatrics and pregnancy. 1. Drugs and the Fetus Extension of drug’s pharmacologic activity Absorption across the placenta Metabolism by the fetus Teratogenicity FDA Classification of Teratogens Category Category Category Category Category A B C D X 1 Category A Category B No evidence of risk in humans Controlled studies show no risk Safe for use in pregnancy Examples: folic acid, levothyroxine Category C Risk cannot be ruled out – risk has been demonstrated in animals but no controlled studies are available in women Benefit may justify risk Examples: albuterol, aspirin, TMP/SMX, ß-blockers, phenothiazines, loop diuretics, guaifenesin, ACE inhibitors (1) Category X Contraindicated in pregnancy Risk clearly outweighs benefit Examples: finasteride, misoprostil, retinoids, warfarin, thalidomide, alcohol, cocaine Either no evidence of risk in animal studies or animal studies reveal risk and risk not demonstrated in well controlled trials Examples: acetaminophen, cephalosporins, penicillins, NSAIDs (1,2), insulin, H-2 blockers Category D Positive evidence of risk Risk usually outweighs benefitexception maybe made for certain situations Examples: benzodiazepines, thiazides, certain oral hypoglycemic agents, lithium, phenytoin, ACE inhibitors (2,3), valproic acid, NSAIDs (3) Routes of Administration Route of administration may influence use of medication Examples inhaled steroids, vaginal creams, topical creams Flagyl® vs Metrogel® Gynazole® vs Diflucan® Flonase® vs prednisone 2 Sources of Drug Information Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and Lactation, 7th ed. Baltimore: Lippincott, Williams and Wilkins (2005) PDR Package insert Epocrates and Lexi-Drug (PDA reference) Drug Therapy of Pregnancy Vitamin / Mineral Supplementation Nausea / Vomiting Diabetes in Pregnancy Depression Asthma Rhinitis Antibiotic Use Folic Acid and Pregnancy A supplement of 0.4 mg of folic acid has been recommended to decrease the risk of neural tube defects Should be started 3 months prior to intended conception and continued throughout pregnancy Patients with a history of affected offspring should take 4 mg/day Drug exposure during pregnancy Many drug exposures occur prior to knowledge of pregnancy – fetus most susceptible Need information – what medication was used, verify pregnancy and gestational age Use appropriate reference material to determine risk Report to pharmaceutical companies Appropriate referral for diagnostic ultrasound Vitamins and Minerals in Pregnancy Prenatal vitamin supplement is recommended – formulation adjusted for needs of and safety in pregnancy Some contain an iron supplement 30 mg elemental iron recommended Most contain additional calcium Non-Pharmacologic Therapies for Nausea / Vomiting Small, frequent high CBH meals Avoid triggers Bedrest Bio-Bands (Sea-bands) Emetrol® – cola syrup Ginger root 3 Pharmacological Treatment Mild Nausea and Vomiting pyridoxine (vitamin B-6) meclizine (Antivert®, Bonine®) dimenhydrinate (Dramamine®) doxylamine (OTC Unisom®) H2 blockers (ranitidine) metoclopramide (Reglan®) Hyperemesis Severe nausea and vomiting resulting in weight loss, electrolyte abnormalities May require hospitalization Can become life-threatening if untreated IV fluids, IV medication Consider vitamin supplements (thiamine and vitamin K) if protracted Diabetes in Pregnancy White’s Classification (cont) D - Diabetes diagnosed before age 10 or length of disease > 20 years or benign retinopathy EF - disease w/ nephropathy H - presence of cardiac disease R - proliferative retinopathy RT - disease with a renal transplant Pharmacologic Treatment (cont) promethazine (Phenergan®) prochlorperazine (Compazine®) ondansetron (Zofran®) droperidol – associated with EKG changes – used only as an inpatient on a telemetry unit Diabetes in Pregnancy White’s Classification A – Gestational Diabetes A1: managed by diet alone A2: managed by diet and insulin B - Diabetes diagnosed after age 20 or length of disease < 10 years C - Diabetes diagnosed between age 10-19 or length of disease for 10-19 years Gestational Diabetes Treatment is definitely indicated for elevated blood sugars that do not respond to modification of diet Insulin is the drug of choice Glyburide has recently been shown to be safe and effective NEJM 10/19/2000 4 Depression Asthma SSRI’s - most common drug class used Asthma course may worsen, improve or remain unchanged during pregnancy Poor asthma control biggest factor leading to poor outcomes OK to use: Prozac®, Paxil®, Zoloft®, Celexa®, Lexapro® Cymbalta® Many cases of neonatal withdrawal reported Start with lowest possible dose Caution with Paxil® use Breastfeeding helps Post-partum depression & breastfeeding Consider Zoloft® or Paxil® Beta-agonists (Albuterol, Salmeterol, Fometerol) Inhaled Corticosteroids (Budesonide, Fluticasone) Theophylline Cromolyn-decocromil Antibiotic Use During Pregnancy Rhinitis (Allergies) Complicates up to 20% of pregnancies Avoid environmental triggers 1st generation antihistamines Chlorpheniramine Tripelennamine 2nd generation antihistamines Loratadine (Claritin®) Cetirizine (Zyrtec®) Fexofenadine (Allegra®) Safe penicillins cephalosporins erythromycin nitrofurantoin Intranasal corticosteroids appear to be safe Antibiotics and Pregnancy contraindications Sulfonamides can displace bilirubin from binding sites and affect folic acid metablolism Do not use in 3rd trimester Tetracyclines cause staining of fetal teeth and bones Fluoroquinolones are associated with joint malformations in animal studies UTI in Pregnancy Common infection during pregnancy Risk of pyelonephritis, sepsis if untreated Benefit of culture and sensitivity Treat with macrodantin, penicillins, cephalosporins, Bactrim® (not third trimester) 5 Parting thoughts #1 Prior to prescribing medication, ask your female patients if they are attempting pregnancy May need to verify with pregnancy testing!!! Use medications with safety information Educate your patients Drugs and Lactation Drug Use During Lactation Overview “Safe” Drugs Drugs to Avoid “Safe” Drugs for use during lactation Most drugs are safe during lactation Typically only 1-2 percent of the maternal dose is secreted in breast milk Again, utilize appropriate references before prescribing to lactating patients Many antibiotics Antihistamines Vitamins Antidepressants – Paxil® with shortest t½ and no active metabolite Domperidone? Treatment of Mastitis Contraceptives and Lactation Dicloxacillin, cephalexin Encourage breastfeeding or pumping No need to pump and discard Infant treated via breastmilk Estrogen containing contraceptives may decrease milk supply Progesterone-only-pills, Depo-Provera®, IUD’s would be appropriate alternatives Breast-feeding alone not adequate for contraception 6 Medications Contraindicated during Breast-feeding Bromocriptine Cocaine, Alcohol, PCP Antineoplastic Agents Cyclophosphamide Methotrexate Radioactive Iodine Lithium, Ergotamine Immunosuppresive Agents Parting thoughts #2 Verify the appropriateness of treatment prior to prescribing medication Verify safety of the medication in question Typically, 1% of medications are excreted in breast milk Counsel your patient regarding risks and benefits Drug Dosing Principles Individualize the dose! mg/kg for most drugs mg/m2 for chemotherapy Make sure that you prescribe the correct units (mg, mcg) Make sure that the parent or caregiver knows how to measure the dose Educate the parents or caregiver Sources of Drug Information for Lactation Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in Pregnancy and Lactation, 7th ed. Baltimore: Lippincott, Williams and Wilkins (2005) Hale, TW. Medications and Mothers’ Milk, Amarillo: Pharmasoft Medical Publishing, 11th ed. (2004) Package insert Epocrates or Lexi-Drug (PDA reference) Drug Therapy in Neonates and Pediatrics Principles of Drug Dosing Sources of Information Routes of Administration Treatment of Common Illnesses Immunizations Sources of Pediatric Drug / Dosing Information Gunn VL, Nechyba C, Barone NA, eds. Harriet Lane Handbook, 17th ed. St. Louis: Mosby, (2005). Taketomo CK, et al., eds. Pediatric Dosage Handbook, 12th ed. Hudson, OH: Lexi-Comp, Inc. (2005). Young TE, Mangum B. Neofax, 18th ed. Raleigh, NC: Acorn Publishing, Inc. (2005) 7 Sources of Pediatric Drug / Dosing Information a Children’s Hospital pharmacy National Poison Control Center: 1-800-222-1222 Dosing Conversion Factors 1 ml = 1 cc 1 tsp =5 ml 1/4 tsp = 1.25 ml 1/2 tsp = 2.5 ml 3/4 tsp = 3.75 ml Routes of Administration Oral Solutions / Suspensions vs Elixirs “Sprinkles” Chewable tablets Rectal Make sure to specify “pediatric” suppositories Pediatric Drug Dosing Look in more than one source if: You are unfamiliar with the drug The drug has a narrow therapeutic range If you can’t find a pediatric drug dosage, perhaps the drug shouldn’t be used. Don’t rely on adult formulas! Pediatric Drug Dosing When writing drug orders for pediatric patients, BE EXPLICIT! Good: 375 mg PO q12h Bad: 37.5 mg/kg q12h Awful: 75 mg/kg/d in 2 divided doses Write legibly ex: ampicillin vs. aminophylline Routes of Administration Topical Increased absorption of topical drugs (proportionately larger skin surface area; increased with inflammation, plastic diapers) Special care with groin and face Parenteral IV preferred in neonates 8 Acetaminophen dosing Treatment of Fever Acetaminophen (Tylenol, Tempra, generics) Drops Elixer Chewable Weight (lbs) 80 mg/0.8 mls 160 mg/tsp 80 mg/tab 6-10 0.4 mls 11-15 0.8 mls 1/2 tsp 1 tab 16-20 1.2 mls 3/4 tsp 1.5 tabs 21-25 1.6 mls 1 tsp 2 tabs 26-30 2.0 mls 1 1/4 tsp 2.5 tabs 31-40 2.4 mls 1 1/2 tsp 3 tabs 41-50 3.2 mls 2 tsp 4 tabs Note: Dosage is every 4 hours not to exceed 5 doses/ 24 hrs Junior chewable tablets are 160 mg/tab Acetaminophen: 10-15 mg/kg/dose max 60 mg/kg/d Ibuprofen: 5-10 mg/kg/dose max 40 mg/kg/day NO ASPIRIN!!! Ibuprofen dosing Cough / Cold Ibuprofen (Motrin, Advil, generics) Weight Pounds 12-17 18-23 24-35 36-47 48-59 60-71 72-95 Age Dose every 6-8 hours--Do not give if child has diarrhea or has been vomiting Oral drops Suspension Chewable Chewable 50 mg/1.25 mls 100 mg/5 mls tablets 50 mg tablets 100 mg Fever Fever Kilos <102.5 >102.5 5.5-7.9 6-11 mos 0.675 mls 1.25 mls 8-10.9 12-23 mos 1.25 mls 2.5 mls 11-15.9 2-3 yrs 2 mls 3.75 mls 16-21.9 4-5 yrs 22-26.9 6-8 yrs 27-31.9 9-10 yrs 32-43.9 11 yrs Fever <102.5 1/4 tsp 1/2 tsp 3/4 tsp 1 tsp 1 1/4 tsp 1 1/2 tsp 2 tsp Fever >102.5 1/2 tsp 1 tsp 1 1/2 tsp 2 tsp 2 1/2 tsp 3 tsp 4 tsp Fever <102.5 Fever >102.5 1 tab 1 1/2 tab 2 tab 2 1/2 tab 3 tab 4 tab 2 tab 3 tab 4 tab 5 tab 6 tab 8 tab Fever <102.5 Fever >102.5 Fever <102.5 Fever >102.5 1/2 tab 1 tab 3/4 tab 1 1/2 tab 1 tab 2 tab 1 cap 2 cap 1 1/4 tab 2 1/2 tab 1 1/4 cap 2 1/2 cap 1 1/2 tab 3 tab 1 1/2 cap 3 cap 2 tab 4 tab 2 cap 4 cap Treatment of Otitis Media Antibiotics Drug selection Duration of therapy Chronic, suppressive therapy Antihistamines / Decongestants No evidence of value Caplets 100 mg Antihistamines Decongestants Expectorants Cough suppressants Treatment of Otitis Media New criteria for treatment of otitis media Mild and moderate cases to be followed expectantly to decrease overuse of antibiotics High-dose amoxicillin x 10 days Single-dose azithromycin (30 mg/kg) 9 Primary Care Associates 1234 Wellness Road Resume Speed, Kansas Phone: 999-1212 Amoxicillin for 25 lb child 40 mg/kg/day in 3 divided doses 25 pounds = 11.4 kg Daily dose = 40 x 11.4 = 456 mg = 450 450 mg/3 doses = 150 mg/dose 150 mg/dose / 125 mg/5 ml = 6 ml Dose: 6 ml tid Name ___Ear infection Emily____________________ Date ____________ Address ____123 Mulberry Ln________________ Age/Wt _18mo/25lbs Rx Amoxicillin susp. 125mg/5ml Disp: 150 ml Sig: 6 ml po tid x 5 days ____________________________ Dispense as Written ______________________ Substitution Permissible Refills __________ Pharyngitis (Strep throat) Usually caused by Group A beta-hemolytic streptococcus Only treat if rapid-screen is positive 10 day antibiotic course 1st choice: Pen-VK or Amoxicillin 2nd choice or PCN allergic: Macrolides or Cephalosporins Acute Bacterial Rhinosinusitis Supportive Therapy Hydration Nasal saline spray and/or gel Steam Rest Analgesia Decongestants Mucolytics Acute Bacterial Rhinosinusitis Initial therapy for mild disease w/o previous abx use: High-dose Augmentin® High-dose amoxicillin Cefpodoxime (Vantin®) Cefuroxime (Ceftin®) Cefdinir (Omnicef®) With prior abx use in previous 4-6 weeks High-dose Augmentin® Ceftriaxone (50 mg/kg/day x 5 days by inj) Allergic Rhinitis Affects 40% of children Risk factors Pollution, maternal smoking, higher social class, non-white race, early intro of foods Environmental control measures Decrease exposure to dander and pollens Filtered vacuum Air conditioner and dehumidifier Wash bedding in hot water every 2 weeks 10 Allergic Rhinitis Pharmacologic treatment Antihistamines (1st gen vs 2nd gen) Inhaled corticosteroids Decongestants Anticholinergic agents Mast cell stabilizers Leukotriene antagonist Oral Corticosteroids Childhood Asthma Beta-agonists Albuterol / Levalbuterol Salmeterol Formoterol (Foradil®) Inhaled corticosteroids Fluticasone (Flovent®) Budesonide (Pulmicort®) Theophylline - children metabolize faster LT modifiers - (Singulair®) vs. Steroids MDIs - for children > 4 yrs Gastroesophageal Reflux presenting symptoms and signs Infants Prednisone Tablets Liquid: 5mg/5ml Prednisolone Tablets Liquid: 5 mg/5 ml and 15 mg/5 ml Older child / adolescent Fussy feedings Arching Irritability Recurrent vomiting Poor weight gain Apnea Poor sleeping Recurrent vomiting Heartburn Esophagitis Dysphagia or refusal to eat Asthma Recurrent pneumonia Upper airway symptoms Gold, BD. Management Algorithm #1…Medscape Pediatrics.12/2004 Reflux True reflux vs spitting up Risk of aspiration in infancy Goals of treatment: eliminate symptoms heal esophagitis manage or prevent complications maintain remission Reflux Non-pharmacologic therapy Feed in upright position Elevate crib mattress Drug therapy Motility agent – Metoclopramide (Reglan®) H2 blockers – Ranitidine (Zantac®) Proton Pump Inhibitors – Prilosec®, Prevacid® 11 Vaccines - CDC 2007 Recommended Childhood Immunization Schedule Benefits of vaccines Prevention of acute illness Prevention of complications of illnesses Improvement in quality of life Prevention of death Herd immunity Prevention of disease outbreaks Reduction in health care costs Contraindications to ALL Vaccines History of anaphylactic reaction to vaccine Concurrent moderate / severe illness +/- fever vomiting, diarrhea, otitis media Vaccines - CDC 2007 Recommended Adolescent Immunization Schedule Simultaneous Administration Increases likelihood that child will be fully immunized No effect on ability of vaccine to confer immunity If not administered simultaneously, live vaccines should be given 4 weeks apart Inactivated vaccines do not interfere with other vaccines and can be given at any time interval Contraindications to live, attenuated vaccines Immunocompromised individuals Pregnancy Receipt of antibody containing products (blood or immunoglobulin) within the last 3-5 months 12 Hepatitis B Perinatal Transmission Perinatal transmission a serious risk for infants born to mothers with hepatitis B 90% of affected infants develop chronic hepatitis 95% of cases acquired at delivery Immunoglobulin available Screening of all pregnant women for hepatitis B - a practice standard Vaccine 85-95% effective Diphtheria, Pertussis, and Tetanus Diphtheria - acute infection that affects tonsillar tissues Pertussis – Whooping cough high morbidity and mortality Tetanus – infects wounds Tetanus vaccine indicated at time of exposure if greater than five years since last booster Haemophilus Influenza type b (HIb) Leading cause of invasive bacterial disease in the US 66% of cases affected children age <15 months Prior to vaccination, 1/200 developed invasive disease by age 5 60% had meningitis and 3-6% died 20-30% with permanent sequelae Hepatitis B and delivery First vaccine dose given to infants before discharge Infants born to HBsAg-positive / HBsAg status unknown mothers receive vaccine plus HBIG at delivery Measles, Mumps, and Rubella Measles presents with cough, fever and rash high morbidity and mortality Mumps infection of parotid and salivary glands, encephalitis and meningitis Rubella - viral infection presents as a rash with fever, lymphadenopathy, and arthralgias congenital rubella can interfere with fetal development Polio Vaccine Trivalent inactivated virus – IPV Oral OPV no longer used Contraindications Avoid during pregnancy unless exposure occurs History of anaphylactic reaction to streptomycin, bacitracin, neomycin 13 Streptococcus pneumoniae (Prevnar®) Varicella Zoster Most common cause of community acquired pneumonia in young children Also causes septicemia and meningitis (5%) mortality rate Causative agent in 30-50% of otitis media Carrier state – 30-50% of preschool children Contraindicated if pt has h/o anaphylactic reaction to gelatin or neomycin Prior to vaccination, 90% of population infected Can result in severe complications and hospitalizations May cause congenital malformations Neonatal infection caused by maternal perinatal infection can be severe (35% mortality) Varicella Zoster (Varivax®) Vaccination Guidelines Influenza Vaccine Live attenuated virus Administer to any susceptible child at or greater than 12 months of age Susceptible children greater than age 13 should receive 2 doses 4 weeks apart MMR-Varicella combo vaccine now available 70 to 90% effective in preventing disease Influenza Vaccine Fluzone®, Fluvirin® For IM administration Contain thimerosal Flumist® Intranasal administration For ages 5-49 yrs Often not covered by insurance ($23.50) Contraindicated if severe allergy to eggs Recommended for all children > 6 mo Administered annually Oct – Dec Dose 6-35 mos: 0.25 ml 3-8 yrs: 0.5 ml Repeat dose in 1 mo if not previously immunized Hepatits A vaccine Recommended for all children at 1yr Should be given to children / adolescents in regions of high risk 2 dose series – at least 6 months between injections VAQTA® - 12 mo or Havrix® - 2 yrs 14 Hepatits A cases in KS Hepatits A cases in MO Hepatits A Cases in the U.S. Vaccines in Pregnancy If indicated, you can give Tetanus Influenza (IM only) Hepatitis B If indicated, give the following before or after pregnancy MMR Varicella Hepatits A Vaccines in the pipeline Human Papillomavirus Gardasil®, Cervarix® Rotavirus Rotateq®, Rotarix® Invasive meningococcal disease Menactra® Immunization Standards Vaccines should be readily available Available for free or nominal charge Immunization screening should be done at all clinical encounters Follow only “true” contraindications Question and educate parents www.immunize.org 15 Reporting Vaccine Adverse Events Health care providers should report serious adverse events to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967. For more information, visit the following site: http://www.vaers.org/ Other information and updates go to www.cdc.gov/nip Parting thought #3 Double check dosing and appropriateness of medication choice Verify references for medication use – if you are unable to find references, the medication probably should not be used Follow CDC guidelines and manufacturers instructions regarding use of vaccines Conclusion 16