ADR & Drug-Drug Interactions

Monitoring and Adverse Drug Reactions in Clinical Trials

Controlled Trials

• Patients are closely monitored in controlled trials with experienced practitioners evaluating them.
• In clinical practice, patients may experience more variability after a drug is approved.
  • Unique treatment due to individual patient characteristics.
  • Example: Alpha-labeled uses of drugs that differ from trial conditions.

Adherence Issues

• Adherence to medication regimens can be suboptimal.
  • Some patients may take medications as intended, while others may not.
• Patients are typically seen less frequently in clinical practice compared to clinical trials, where scheduled monitoring occurs.

Role of the FDA in Monitoring ADRs

• The FDA can respond to emerging information regarding adverse drug reactions (ADRs) by:
  • Updating product labeling including package inserts.
  • Including a black box warning at the top of the insert for serious adverse events.
  • Requiring the implementation of a Risk Evaluation and Mitigation Strategy (REMS) for drugs with a black box warning.
  • Possible removal of drugs from the market if significant safety concerns arise.

REMS Details

• REMS may be required even before the drug is available on the market.
• Components of REMS may include:
  • Medication guides for prescribers.
  • Communications about risks to prescribers.
  • Special training for prescribers utilizing the medication.

Example of Adverse Drug Reaction

• Case Study: 33-year-old male with increasing fatigue and appetite loss 10 days after starting Trovium for an infection.
  • Physical exam showed mild jaundice and elevated liver function tests (LFTs).
• Literature Search Findings:
  • Original labeling indicated possible LFT increases after 21 days of therapy; safety beyond four weeks unstudied.
  • Trovium was widely prescribed without reports of liver injury in premarketing trials.
  • After marketing, numerous liver injury reports prompted FDA action to update labeling and restrict usage.
  • By 2002, Trovium was discontinued due to safety concerns.

Reporting of Adverse Drug Reactions

• Pharmacists can report ADRs.
  • Reporting through FDA MedWatch is encouraged but not mandatory for pharmacists.
  • Physician reporting is not mandatory either.
  • However, manufacturers are required to report ADRs.

Limitations of Pre-marketing Data

• Product labeling is mostly based on pre-marketing data, which has significant limitations:
  • Small sample sizes from clinical trials.
  • Trials have a limited duration and may not capture rare or long-term ADRs.
  • Generally higher adherence in trials than in real-world settings.
• Post-marketing data is essential for discovering long-term safety and efficacy beyond initial studies.

Adverse Drug Reaction Evaluation Strategy

Patient Assessment

• For assessing ADRs, consider key factors about the patient:
  • Age (pediatric or geriatric).
  • Liver and kidney function.
  • Allergy history including specific allergies.

Drug Assessment

• Questions include:
  • Onset of the drug therapy and dosing details (any changes?).
  • Concurrent medications (any recent changes?).
  • Laboratory tests related to ADRs (e.g., liver tests).

Literature Search

• Begin with tertiary literature for drug information:
  • Examples include Lexicomp, Clinical Pharmacology, Micromedex.
• Review references for recency and relevance.

Secondary and Primary Literature

• Use secondary resources like PubMed for primary literature, such as:
  • Animal studies and observational studies like case-control or cohort studies.
  • Most importantly, focus on case reports which provide anecdotal evidence of ADRs.

Understanding Case Reports

• Case reports are detailed accounts of individual patient experiences with specific drugs.
  • They describe new or unusual effects and can identify potential ADRs.
  • Often published in journals with a structured format:
  • Abstract summarizing the article.
  • Introduction detailing drug and effects.
  • Case presentation with diagnosis, treatment, and outcomes.
  • Discussion comparing findings with prior reports.

Importance of Temporal and Dose Relationships

• Temporal Relationship: Time between drug administration and ADR onset.
  • Essential for establishing causation.
• Dose Relationship: Changes in drug dosage impacting reactions.
• D-Challenge and Re-Challenge: Evaluating the resolution of symptoms post-drug withdrawal and re-administration effects.

Assessing Causality with the Naranjo Algorithm

• Naranjo Algorithm assesses the likelihood that an ADR relates to a drug with 10 yes/no questions.
  • Gives a score ranging from less than 1 to about 9, indicating levels of probability from unlikely to probable.
  • Recognizes that most cases will be assessed without rechallenge due to ethical concerns.

Summary of Key Points on Adverse Drug Reactions

• Premarketing data is often limited, highlighting the importance of pharmacist and manufacturer reporting for ADRs.
• Case reports are crucial for identifying ADRs and interactions, often being the initial evidence for emerging safety issues.
• The Naranjo algorithm is widely accepted to assess ADR causality, but understanding the limitations and context of the data is essential.

Upcoming Assignments

• Future assignments will involve evaluating case reports utilizing the Naranjo algorithm to determine ADR causality.