Overview and Regulatory Issues Overview and Regulatory Issues Regarding Anesthetic Agents for Regarding Anesthetic Agents for Pediatric PatientsPediatric Patients

Anesthetics and Life Support Drugs Anesthetics and Life Support Drugs Advisory Committee MeetingAdvisory Committee MeetingMarch 29, 2007March 29, 2007

Arthur Simone, MD, PhD Arthur Simone, MD, PhD Division of Anesthesia, Analgesia and Division of Anesthesia, Analgesia and Rheumatology ProductsRheumatology Products

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

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The IssueThe IssueSynaptogenesis (brain growth spurt)• Highly regulated period of brain development• A process that appears conserved among

species– Rodents: 2 days before to 2 weeks after birth– Humans: 3rd trimester to ~ 3 years of age

• Second spurt observed in humans during late adolescence

• Adversely affected by environmental conditions

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The IssueThe Issue• Glutamate and γ-amino-butyric acid (GABA)– Non-synaptic trophic factors– Promote neuronal arbor elaboration

• GABA-receptor stimulation and N-methyl D-aspartate (NMDA) receptor blockade– Deleterious effects on neural development– Apoptosis - programmed cell death• Single cell• Shrunken, preserved plasma membrane• Non-inflammatory

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Receptor Activity of Commonly Receptor Activity of Commonly Used Anesthetic AgentsUsed Anesthetic Agents

Anesthetic Agent NMDA antagonist GABA-mimetic -Opioid agonist Volatile Anesthetics Halothane / 0 +++ 0 Isoflurane / 0 +++ 0 Desflurane / 0 +++ 0 Enflurane / 0 +++ 0 Sevoflurane / 0 +++ 0 Injectable Anesthetics Propofol 0 +++ 0 Barbiturates 0 +++ 0 Etomidate 0 +++ 0 Benzodiazepines 0 +++ 0 Ketamine / 0 0 Medical Gases Nitrous Oxide +++ 0 Opioid analgesics Morphine / 0 0 +++ Methadone 0 +++ Meperidine / 0 0 +++ Fentanyl / 0 0 +++ Other Sedative Hypnotics Chloral Hydrate +++ 0 Trichloroethanol +++ 0 Ethanol +++ 0

Key: +++ / 0 + / 0 0

Strong antagonism within the clinically relevant range based on available in vitro data Strong potentiation within the clinically relevant range based on available in vitro data Little antagonism within the clinically relevant range based on available in vitro data Little potentitation within the clinically relevant range based on available in vitro data No compelling data to support activity at this site within the clinically relevant range

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Anesthesia and the Anesthesia and the Vulnerable PatientVulnerable Patient

• Exposures– Maternal surgery– In-utero surgery – Labor and delivery/Cesarian section– Surgical procedures from birth to age 3 years

• Alternative Therapies– Neuraxial/regional/local anesthesia – Opioid anesthesia– No anesthesia– Delay surgery

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Commonly Used Anesthetic Commonly Used Anesthetic AgentsAgents

Sedative Hypnotics Inhalation Anesthetics Local Anesthetics Thiopental Halothane Bupivacaine Methohexital Isoflurane Lidocaine Propofol Enflurane Mepivacaine Ketamine Desflurane Chloroprocaine Etomidate Sevoflurane Procaine Phenobarbital Nitrous Oxide Tetracaine Chloral hydrate Etidocaine Clonidine Non-Opioid Analgesics Ropivacaine Dexmedetomidine Ketorolac Acetaminophen Muscle Relaxants Other Ibuprofen Atracurium Promethazine cis-atracurium Droperidol d-tubocurarine Scopolamine Opioid Analgesics Doxacurium Fentanyl Succinylcholine Sufentanil Mivacurium Alfentanil Pancuronium Benzodiazepines Remifentanil Pipercuronium Midazolam Morphine Rocuronium Lorazepam Meperidine Vecuronium

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Commonly Used Anesthetic Agents Commonly Used Anesthetic Agents With Pediatric Specific LabelingWith Pediatric Specific Labeling

Sedative Hypnotics Inhalation Anesthetics Local Anesthetics Thiopental Halothane Bupivacaine Methohexital Isoflurane Lidocaine Propofol Enflurane Mepivacaine Ketamine Desflurane Chloroprocaine Etomidate Sevoflurane Procaine Phenobarbital Nitrous Oxide Tetracaine Chloral hydrate Lidocaine-Prilocaine Clonidine Non-Opioid Analgesics Ropivacaine Dexmedetomidine Ketorolac Acetaminophen Muscle Relaxants Other Ibuprofen Succylcholine Promethazine Atracurium Droperidol cis-atracurium Scopolamine Opioid Analgesics d-tubocurarine Fentanyl Doxacurium Sufentanil Mivacurium Alfentanil Pancuronium Benzodiazepines Remifentanil Pipercuronium Midazolam Morphine Rocuronium Lorazepam Meperidine Vecuronium

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Commonly Used Anesthetic Agents Commonly Used Anesthetic Agents With Any Pediatric Specific Labeling With Any Pediatric Specific Labeling

for Ages for Ages ≤ 3 years≤ 3 yearsSedative Hypnotics Inhalation Anesthetics Local Anesthetics Thiopental Halothane Bupivacaine Methohexital Isoflurane Lidocaine Propofol Enflurane Mepivacaine Ketamine Desflurane Chloroprocaine Etomidate Sevoflurane Procaine Phenobarbital Nitrous Oxide Tetracaine Chloral hydrate Lidocaine-Prilocaine Clonidine Non-Opioid Analgesics Ropivacaine Dexmedetomidine Ketorolac Acetaminophen Muscle Relaxants Other Ibuprofen Succinylcholine Promethazine Atracurium Droperidol cis-atracurium Scopolamine Opioid Analgesics d-tubocurarine Fentanyl Doxacurium Sufentanil Mivacurium Alfentanil Pancuronium Benzodiazepines Remifentanil Pipercuronium Midazolam Morphine Rocuronium Lorazepam Meperidine Vecuronium

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Classification of Drug Products for Classification of Drug Products for Use During PregnancyUse During Pregnancy

21 CFR §201.57• A - human studies show no risk• B - animal studies show risk but human

studies do not• C - animal studies show risk but no human

studies conducted, or no studies at all• D - evidence of human fetal risk• X - studies have demonstrated animal or

human fetal abnormalities and risk outweighs any possible benefit.

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Commonly Used Anesthetic Commonly Used Anesthetic Agents – With a Pregnancy Agents – With a Pregnancy

Classification of A or BClassification of A or B• Methohexital• Propofol• Enflurane• Desflurane• Sevoflurane• Lidocaine• Lidocaine-Prilocaine• Ropivacaine• cis-atracurium

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Milestones for Drug RegulationMilestones for Drug Regulation• 1934 - Thiopental (clinical use; never approved for parenteral)• 1938 - The Federal Food, Drug, and Cosmetic (FDC) Act• 1942 - Meperidine• 1958 - Halothane• 1960 - Methohexital • 1962 - Kefauver-Harris Drug Amendments • 1966 - NAS and NRC to assess efficacy of 4,000 drugs approved 1938-1962• 1968 - FDA forms Drug Efficacy Study Implementation

(DESI) to implement recommendations of the NAS• 1968 - Fentanyl• 1970 - Ketamine• 1971 - National Center for Toxicological Research established• 1979 - 1992 – Isoflurane, Etomidate, Midazolam, Propofol, Desflurane• 1994 - Regulations promulgated stating that there must be

a pediatric use section in the label• 1995 - Sevoflurane• 1997 - Food and Drug Modernization Act• 1998 - Pediatric Rule• 2002 - The Best Pharmaceuticals for Children Act • 2003 - Pediatric Research Equity Act

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Securing Pediatric IndicationsSecuring Pediatric Indications• Drug is initially approved for adult use.• Preclinical evaluation in juvenile animals is not

always required.– Guidance for Industry: “Nonclinical Safety

Evaluation of Pediatric Drug Products” (Feb., 2006)

• Pediatric clinical trials are primarily designed for determining efficacious dosing requirements.

• Assessment of safety – findings from adult trials and new findings from pediatric clinical trials

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AlternativesAlternatives

• Local anesthetics• Narcotic-only anesthesia• No anesthesia/sedation• Delay procedure

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Local AnestheticsLocal Anesthetics

• Topical, regional, and neuraxial anesthesia may be suitable for some procedures.

• Toxicities in pediatric patients have not been fully elucidated.

• Sedation is generally utilized for anxiolysis and amnesia.

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OpioidsOpioids

• May be suitable for some procedures.• Toxicities for pediatric patients have

not been fully elucidated.• Sedation is generally utilized for

anxiolysis and amnesia.

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No AnesthesiaNo Anesthesia• May work for some procedures• Research demonstrates

– Morphological changes in rodent brains– Premature infants show metabolic stress responses

post operatively that can be blocked by intravenous opioids.

– The increasing crying and behavioral changes occur for days after circumcision can be blocked with the use of regional anesthesia.

– 4- to 6-month old infants circumcised without analgesia had higher pain scores than those circumcised with analgesia as measured by observable indicators such as facial expression, length of crying, and body movement

– by 6 months of age, children demonstrate anticipatory fear when taken to places where they experienced pain in the past

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AERS DatabaseAERS Database

• Post-approval safety data collection• Limitations– Voluntary– Submitter status– Data captured• Timing of adverse event• Nature of events• Missing data

– Numerator/Denominator

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Ketamine and AERS DatabaseKetamine and AERS Database

Office of Surveillance and Epidemiology• Between approval and 1-29-07• 153 pediatric (≤ 16 years old) reports• SOCs selected:–Musculoskeletal– Nervous– Psychiatric

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Ketamine and AERS DatabaseKetamine and AERS Database• 58 reports found– 1970-79 (n=9)– 1980-89 (n=5)– 1990-99 (n=22)– 2000-06 (n=22)

• There were 4 fatalities. • 25 reports involved at least one other

NMDA/GABA acting anesthetic

20Anesthetics and Life Support Drugs Advisory Committee Anesthetics and Life Support Drugs Advisory Committee March 29, 2007March 29, 2007

Ketamine and AERS DatabaseKetamine and AERS Database

• convulsions (n=9) • hallucination (n=6)• drug ineffective (n=8) • medication error (n=6)• sedation (n=8) • abnormal dreams (n=5)• pyrexia (n=7) • anesthetic complication (n=5)• bradycardia (n=6) • coma (n=4)

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Where do we stand?Where do we stand?

• A safety signal has been identified in animals for many drugs used to provide sedation and anesthesia.

• The relevance of the animal findings to pediatric patients is unknown.

• The need to provide sedation and anesthesia cannot be avoided in many situations.

• There is no available alternative therapy proven to be safer.