What Is the Orange Book?
The Orange Book is the common name for the U.S. Food and Drug Administration’s (FDA’s) database titled Approved Drug Products With Therapeutic Equivalence Evaluations. It is the FDA’s official list of human prescription and over‑the‑counter drug products that have been approved as both safe and effective. The Orange Book is used widely by clinicians, pharmacists, patients, generic drugmakers, and intellectual‑property practitioners to check approved uses, availability of generics, patents, and exclusivity periods.
Key takeaways
– The Orange Book lists FDA‑approved drug products that have demonstrated both safety and efficacy. Products withdrawn for safety or efficacy reasons are excluded. (FDA)
– It contains therapeutic equivalence evaluations (TE codes) that indicate whether a generic product is considered substitutable for a brand product. (FDA)
– The Orange Book is available free online and is updated daily for many items (e.g., generic approvals, patent changes). It is also available in PDF and print. (FDA)
– Generic manufacturers seeking approval file an Abbreviated New Drug Application (ANDA) and must demonstrate bioequivalence to the reference listed drug. (FDA)
– Patent terms and exclusivity periods are different: typical patent terms are 20 years from U.S. filing; regulatory exclusivities include New Chemical Entity (NCE) and orphan‑drug exclusivities (NCE ≈ 5 years; orphan ≈ 7 years). (FDA)
Understanding the Orange Book — what it contains and what it doesn’t
– Approved products: The Orange Book lists drug products that the FDA approves as safe and effective for their labeled uses. Drugs removed from the market for safety or efficacy reasons are not included. A product under regulatory action may still appear while proceedings continue. (FDA)
– Active ingredients and dosage forms: Entries list the active ingredient(s), dosage forms (tablets, capsules, solutions, etc.), and approved strengths.
– Therapeutic equivalence evaluations: The Orange Book assigns TE codes to listed drug products. These codes indicate whether products are considered pharmaceutically and therapeutically equivalent for substitution purposes (for example, generic substitution at the pharmacy). Consult FDA guidance for full TE code meanings. (FDA)
– Patent and exclusivity information: For many brand products the Orange Book includes patents and periods of marketing exclusivity that can affect when and how a generic can be introduced. (FDA)
How drugs get listed in the Orange Book
1. Clinical development: Drugmakers run clinical trials (Phase 1 through Phase 3) to assess safety and efficacy. Phase 3 trials use larger patient samples to establish effectiveness versus placebo or comparator. (FDA)
2. New Drug Application (NDA): If trials are successful, the manufacturer submits an NDA (or a Biologics License Application for biologics) to the FDA for approval.
3. Approval and listing: When the FDA approves the drug for specific indications, the product is added to the Orange Book. The Office of Generic Drugs uses the TE evaluation process to assign equivalence codes. (FDA)
Using the Orange Book — practical steps and examples
The Orange Book is searchable online. Below are practical, step‑by‑step instructions for common users.
A. For patients and clinicians: find whether a generic exists and check approved uses
1. Go to the FDA’s Orange Book search page (Approved Drug Products With Therapeutic Equivalence Evaluations).
2. Search by active ingredient (recommended) or by proprietary (brand) name. Example: to check for generics of Prozac, search “fluoxetine hydrochloride.”
3. Review the listed dosage forms and strengths; note any discontinued forms and whether they were discontinued for safety/efficacy reasons.
4. Look for listed therapeutic equivalence codes (TE codes) next to generic listings—these indicate whether the listed generics are considered substitutable.
5. Check the “Approved Uses” to confirm the indication(s) the product is approved for. (FDA)
B. For pharmacists: verify substitution eligibility
1. Search the Orange Book for the active ingredient and the specific dosage form/strength you plan to dispense.
2. Confirm the TE code for the generic product. Pharmacies typically rely on FDA TE codes and state substitution laws to determine whether substitution is permitted.
3. Check for any patent or exclusivity listings that might legally prevent substitution; consult legal counsel or your state board of pharmacy when unsure. (FDA)
C. For generic drug manufacturers: steps toward ANDA approval
1. Identify the reference listed drug (RLD) in the Orange Book (search by active ingredient).
2. Prepare an Abbreviated New Drug Application (ANDA). The ANDA must show that the proposed generic is pharmaceutically equivalent and bioequivalent to the RLD (i.e., no clinically meaningful differences). (FDA)
3. Address patent and exclusivity status listed in the Orange Book:
– File patent certifications per the Hatch‑Waxman framework (see FDA guidance on patents and exclusivity). Depending on the certification type, litigation under the Hatch‑Waxman provisions may follow. (FDA)
4. Submit the ANDA to the FDA. If approved, the generic will be listed in the Orange Book. (FDA)
D. For IP attorneys and business analysts: check patent and exclusivity details
1. Search the Orange Book entry for the brand product and expand the patents/exclusivity section.
2. Note patent numbers and listed expiration dates. Keep in mind:
– Statutory patent term is generally 20 years from U.S. filing date, but term adjustments, extensions (e.g., patent term extensions to compensate for regulatory delay), and other factors can modify effective remaining patent life. (FDA)
– Regulatory exclusivity (e.g., NCE and orphan) is separate from patents and can block generic approval/market entry even with no active patents. (FDA)
3. For a full IP strategy, corroborate Orange Book listings with USPTO records and the actual patent documents; Orange Book listings are informational and reflect what the NDA holder provided to FDA. (FDA)
Interpreting specific Orange Book indicators
– Discontinued products: Entries may show discontinued forms/strengths. The Orange Book sometimes indicates whether discontinuation was not for safety/efficacy reasons.
– Therapeutic equivalence (TE) codes: These are critical when determining substitutability. For meanings of specific codes, consult the Orange Book TE code guidance on the FDA site. (FDA)
– Patents vs. exclusivity: Patents are private‑law rights granted by the U.S. Patent and Trademark Office. Exclusivity is a regulatory protection provided by the FDA for certain classes of drugs and is independent of patent status. The Orange Book lists both where applicable. (FDA)
How often and where the Orange Book is updated
– The electronic Orange Book is updated daily for many items (including generic approvals and patent updates). Some other information (e.g., new NDA approvals, discontinued products) may be updated monthly. The electronic database is the most current source. (FDA)
Practical checklist (quick)
– Patients/clinicians who want a cheaper alternative:
1. Search the Orange Book by active ingredient.
2. Confirm available generics and TE codes.
3. Discuss substitution with the prescribing clinician and pharmacist.
– Generic manufacturer evaluating market entry:
1. Identify RLD and its patents/exclusivities in the Orange Book.
2. Plan and perform bioequivalence studies.
3. Prepare and submit ANDA; address patent certifications required under Hatch‑Waxman.
– IP/legal team performing diligence:
1. Pull Orange Book listings for RLD.
2. Cross‑check listed patents with USPTO and patent documents for claims and term.
3. Confirm any FDA exclusivity that could impede generic approval.
Fast facts
– Official title: Approved Drug Products With Therapeutic Equivalence Evaluations (commonly “Orange Book”). (FDA)
– Online access: Free, searchable electronic database; PDF and print available. Electronic version updated most frequently. (FDA)
– Generic approval pathway: Abbreviated New Drug Application (ANDA) requiring bioequivalence demonstration. (FDA)
– Typical exclusivity durations mentioned by FDA guidance: New Chemical Entity ≈ 5 years; Orphan Drug ≈ 7 years. (FDA)
– Statutory patent term: generally 20 years from U.S. filing date, subject to adjustments and extensions. (FDA)
Limitations and cautions
– Orange Book entries reflect FDA approvals and information submitted to the FDA; they are not a substitute for reviewing full patent documents or consulting legal counsel on patent or regulatory strategy.
– State laws and pharmacy practice rules govern actual substitution at the pharmacy level—Orange Book TE codes are only one element in substitution decisions.
– The Orange Book covers approved human drug products; biologics and some other products are regulated differently (e.g., licensed biologics may be listed in the Purple Book).
Sources and further reading
– U.S. Food & Drug Administration. “Approved Drug Products With Therapeutic Equivalence Evaluations | Orange Book.” (Accessed Aug. 26, 2021.)
– U.S. Food & Drug Administration. “Step 3: Clinical Research.” (Accessed Aug. 26, 2021.)
– U.S. Food & Drug Administration. “Abbreviated New Drug Application (ANDA).” (Accessed Aug. 26, 2021.)
– U.S. Food & Drug Administration. “Prozac” (product page). (Accessed Aug. 26, 2021.)
– U.S. Food & Drug Administration. “Frequently Asked Questions on Patents and Exclusivity.” (Accessed Aug. 26, 2021.)
– U.S. Food & Drug Administration. “Frequently Asked Questions on The Orange Book.” (Accessed Aug. 26, 2021.)
– Investopedia. “Orange Book” (background summary based on FDA material).
Editor’s note: The following topics are reserved for upcoming updates and will be expanded with detailed examples and datasets.