In Japan, the pharmaceutical package insert (添付文書 - tenpu bunsho) is more than just a leaflet accompanying a drug; it is a critical legal and medical document that underpins the safe and effective use of pharmaceuticals. Governed by the "Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices" (PMD Act or Yakkiho), the package insert serves as the primary source of official information for healthcare professionals (HCPs). Recent regulatory updates, including a mandatory notification system and a shift towards electronic provision, have further underscored its importance. Simultaneously, the complex issue of "off-label use" (適応外使用 - tekiōgai shiyō)—the use of an approved drug for an unapproved purpose—is closely tied to the information, or lack thereof, within these inserts, carrying significant legal implications for both prescribers and Marketing Authorization Holders (MAHs).

The Package Insert: Legal Basis and Core Purpose

The PMD Act mandates the provision of package inserts for pharmaceuticals. Article 52 requires Marketing Authorization Holders (MAHs) to ensure that containers or wrappers of pharmaceuticals they market are accompanied by package inserts containing necessary information, unless otherwise specified by MHLW Ordinance.

Purpose and Content (PMD Act, Article 50 and Article 52):
The fundamental purpose of the package insert is to provide HCPs with comprehensive, accurate, and up-to-date information necessary for the proper use of the drug. According to Article 52, Paragraph 1, this information must be based on the latest scientific knowledge and is crucial for guiding prescribing decisions, patient counseling, and managing adverse events.

The MHLW provides detailed guidance on the content and format of package inserts, notably through the "Guidance on Package Inserts for Prescription Drugs, etc." (医療用医薬品の添付文書等の記載要領について). This guidance is periodically updated, with significant revisions implemented, for example, based on a 2017 notification that became fully effective in 2019, and subsequent clarifications. Key sections typically include:

• Basic Product Information: Name of the product (brand and non-proprietary), composition (active ingredients and major excipients), and pharmaceutical formulation.
• Indications and Usage (効能・効果 - Kōnō・Kōka): The specific diseases or conditions for which the drug is approved.
• Dosage and Administration (用法・用量 - Yōhō・Yōryō): Approved dosage regimens, routes of administration, and duration of treatment.
• Warnings (警告 - Keikoku): Prominently displayed, often in a boxed format, highlighting serious or life-threatening risks.
• Contraindications (禁忌 - Kinki): Situations or patient characteristics where the drug must not be used due to high risk of harm.
• Precautions for Use:
  • Careful Administration (慎重投与 - Shinchō Tōyo): Conditions or patient groups requiring careful consideration and monitoring if the drug is used.
  • Important Basic Precautions (重要な基本的注意 - Jūyōna Kihonteki Chūi): Essential precautions that HCPs must observe during treatment.
• Drug Interactions: Clinically significant interactions with other drugs, foods, or substances.
• Adverse Reactions (副作用 - Fukusayō): A comprehensive list of known side effects, often categorized by frequency and System Organ Class (SOC). This section is continuously updated based on post-marketing surveillance.
• Use in Specific Populations: Guidance for use in pediatric patients, geriatric patients, pregnant or lactating women, and patients with renal or hepatic impairment.
• Overdosage: Information on symptoms and management of overdose.
• Pharmacological Information: Summary of pharmacokinetics (absorption, distribution, metabolism, excretion) and pharmacodynamics (mechanism of action).
• Clinical Study Results: A summary of key clinical trial data supporting the drug's efficacy and safety for approved indications.
• Handling, Storage, and Stability: Instructions for proper storage and handling.
• MAH Information: Name and address of the Marketing Authorization Holder.
• Approval Date and Revision Dates: Date of initial marketing approval and dates of any subsequent revisions to the package insert.

The Package Insert Notification System (添付文書の届出制)

A significant development under the 2014 PMD Act was the introduction of a mandatory notification system for package inserts (PMD Act, Article 52-2 for pharmaceuticals). This system was implemented to enhance regulatory oversight and ensure the timeliness and accuracy of information provided to HCPs.

Key Features:

1. Pre-Marketing/Pre-Change Notification: For designated pharmaceuticals (primarily prescription drugs and "guidance-requiring" Over-The-Counter drugs), MAHs must notify the MHLW (submissions are typically made to the Pharmaceuticals and Medical Devices Agency - PMDA) of the contents of the package insert before they begin marketing the product. Similarly, any subsequent revisions to the package insert must also be notified before the revised information is implemented and disseminated.
2. Immediate Public Disclosure: Upon submission of the notification, the MAH is obligated to immediately make the contents of the notified package insert publicly available. This is primarily done through the PMDA's website, where package inserts are accessible to HCPs and the public.
3. Rationale: This system aims to:
   • Strengthen the MHLW/PMDA's ability to oversee the information provided by MAHs.
   • Ensure that package inserts are consistently based on the latest scientific findings and risk assessments.
   • Facilitate the rapid dissemination of updated safety information, including new warnings or adverse reactions.

Transition to Electronic Package Inserts (電子化された添付文書)

In a major shift aimed at improving accessibility and ensuring timely updates, Japan transitioned to a system where electronic package inserts became the primary means of provision. Effective from August 1, 2021, MAHs are, in principle, no longer required to physically include paper package inserts with all pharmaceutical products. Instead:

• Product packaging typically includes a GS1 DataBar (a type of barcode) that, when scanned by a dedicated app or device, links directly to the latest version of the package insert on the PMDA's website or the MAH's designated information portal.
• HCPs and pharmacies are expected to access the most current information electronically.
• Paper versions of the package insert are generally to be provided by the MAH or pharmacy only upon specific request from an HCP or patient.

This move is intended to ensure that users always have access to the most up-to-date information (as electronic versions can be updated more rapidly than printed stock), reduce paper waste, and streamline the information dissemination process.

"Off-Label Use" (適応外使用 - Tekiōgai Shiyō) of Pharmaceuticals

"Off-label use" refers to the practice of prescribing or administering an approved pharmaceutical product for an indication, in a dosage regimen, for a patient population, or via a route of administration that is not included in its MHLW-approved package insert.

Prevalence and Rationale:
Off-label use occurs in various medical fields, often driven by:

• Unmet medical needs where no approved treatment exists for a specific condition or patient subgroup.
• Emerging scientific evidence or clinical experience suggesting potential benefits for an unapproved use, particularly in rapidly evolving fields like oncology or for rare diseases.
• The time lag between new scientific discoveries and the formal process of updating a drug's approved label.

Legal and Regulatory Standing of Off-Label Use

The legal status of off-label use in Japan is nuanced:

• Physician's Discretion: The PMD Act does not explicitly prohibit physicians from exercising their clinical judgment to use a drug off-label if they believe it is in the best interest of their patient, based on sound medical reasoning and available evidence. This is considered part of a physician's discretionary scope of practice.
• MAH Prohibition on Promotion: Marketing Authorization Holders are strictly prohibited by the PMD Act (Article 68) from promoting or advertising their products for any unapproved (off-label) uses.
• Medical Malpractice and Liability: This is the primary area of legal risk for physicians engaging in off-label prescribing.
  • The Package Insert as a Standard of Care: The information and warnings contained in the approved package insert are considered by Japanese courts to represent a key standard of medical care.
  • Presumption of Negligence: A pivotal Supreme Court judgment on January 23, 1996 (Saikōsai Dai-san Shōhōtei Hanketsu, Minshū Vol. 50, No. 1, p. 1) established that if a physician deviates from the precautions or usage instructions stated in a drug's package insert (which includes off-label use) and an adverse event or patient harm occurs, the physician's negligence is presumed.
  • "Special Justifiable Reason" (特段の合理的理由 - Tokudan no Gōriteki Riyū): To rebut this presumption of negligence, the physician must demonstrate that there was a "special justifiable reason" for deviating from the package insert. The burden of proving such a reason falls on the physician. This justification is assessed based on:
    • The medical standards prevalent at the time of treatment.
    • The specific condition and circumstances of the patient (e.g., severity of illness, lack of effective approved alternatives, urgency).
    • Supporting scientific evidence for the off-label use (e.g., reputable medical literature, established clinical guidelines from academic societies, even if not formally regulator-approved for that specific use).
    • A careful benefit-risk assessment for that particular patient.
• Informed Consent: Obtaining comprehensive informed consent is absolutely critical before initiating off-label treatment. The physician has a heightened duty to explain to the patient:
  • That the proposed use is "off-label" (i.e., not officially approved by regulatory authorities for this specific purpose).
  • The rationale for recommending the off-label use.
  • The potential benefits and known risks based on available evidence.
  • The fact that efficacy and safety for this specific off-label use have not been confirmed by the MHLW.
  • Any alternative approved treatments and their risks/benefits.
    Failure to obtain adequate informed consent can be an independent basis for liability, even if the off-label treatment itself was medically justifiable.

Reimbursement for Off-Label Use

Generally, off-label use of pharmaceuticals is not eligible for reimbursement under Japan's National Health Insurance (NHI) system. This can create a significant financial burden for patients. However, some exceptions and pathways exist:

• System for Evaluating Medical Care with Unapproved Drugs/Indications (保険適用外使用に係る医療の評価療養制度): Japan has a system known as "Patient-Proposed Health Services" (患者申出療養制度 - kanja mōshide ryōyō seido) and previously, a system for "Advanced Medical Care" (先進医療 - senshin iryō), which can allow certain off-label uses with promising evidence to be conducted within a framework where patient co-payment covers the unapproved drug/procedure while other standard care components are reimbursed. Successful outcomes under these systems can sometimes pave the way for formal label expansion.
• MHLW Notifications: In some instances, based on strong scientific evidence and public health needs (often following petitions from medical societies), the MHLW may issue notifications permitting NHI reimbursement for specific, well-defined off-label uses of certain drugs.

Institutional Oversight

There is an increasing expectation, particularly for larger medical institutions like "Specified Function Hospitals" (特定機能病院 - tokutei kinō byōin), to have internal governance mechanisms for off-label drug use. As per amendments to the Medical Care Act (医療法 - Iryōhō), these hospitals are required to establish systems for systematically grasping the status of unapproved/off-label drug use, evaluating its necessity, and ensuring patient safety. This often involves review by institutional ethics committees or drug and therapeutics committees, especially for novel, high-risk, or systematic off-label applications.

Package Inserts, Risk Management Plans (RMPs), and Post-Marketing Safety

Package inserts are integral to a pharmaceutical product's Risk Management Plan (RMP - 医薬品リスク管理計画 - iyakuhin risuku kanri keikaku). RMPs are comprehensive documents that MAHs must prepare and implement to identify, characterize, prevent or minimize risks associated with their products.
Information gathered through post-marketing surveillance (GVP activities), including adverse drug reactions observed during both on-label and off-label use (if reported to the MAH), is continuously evaluated. Significant new safety findings must be used to update the package insert and other risk communication materials in a timely manner, following the notification procedures.

Conclusion

The pharmaceutical package insert in Japan is a legally significant document that serves as a cornerstone for ensuring the safe and effective use of medicines. The mandatory notification system and the shift to electronic provision have modernized how this vital information is managed and disseminated. While the PMD Act allows physicians the discretion to use drugs off-label based on their clinical judgment, such use is fraught with potential legal liability if patient harm occurs and the deviation from the approved package insert cannot be robustly justified by prevailing medical standards and a thorough benefit-risk assessment for the individual patient. Comprehensive informed consent is paramount in such situations. For Marketing Authorization Holders, the responsibilities are clear: ensure the accuracy and currency of package inserts through diligent updates and regulatory notification, and strictly refrain from any promotion of unapproved, off-label uses. Navigating these interconnected aspects of pharmaceutical regulation is crucial for all stakeholders involved in healthcare in Japan.