BFAD Circular on Labeling of COX-2 Inhibitors and NSAIDs

Purpose: revised warnings on NSAIDs

BFAD requests manufacturers to revise package inserts (including boxed warnings) to highlight potential cardiovascular risk and serious life-threatening gastrointestinal (GI) bleeding associated with COX-2 inhibitors and NSAIDs.
BFAD requires clearer patient-facing information so patients are reminded of the limited dose and duration of treatment consistent with package instructions.
BFAD targets both practitioner guidance and public/consumer information through mandated patient leaflets and drugstore posters for OTC products.
BFAD emphasizes stronger labeling for products where the risks require prominent warnings and specific contraindications.

Coverage: products covered and excluded

The Circular covers marketed selective COX-2 inhibitor drugs, including Celebrex and Arcoxia and other selective COX-2 inhibitors such as celecoxib and etoricoxib.
The Circular covers both prescription and over-the-counter (OTC) non-prescription nonsteroidal anti-inflammatory drugs (NSAIDs).
The Circular provides separate labeling directions for prescription nonselective NSAIDs and for OTC NSAIDs.
Aspirin (ASA) is exempted from the directive.
Paracetamol is not included in the directive since it is used as an antipyretic and analgesic for mild to moderate pain.

Timing and implementation instructions

BFAD requires manufacturers to revise the labels (package inserts) of all marketed selective COX-2 inhibitors and NSAIDs subject to the Circular’s directions.
The black box warning for selective COX-2 inhibitor inserts must be placed on the first page of the insert, after posology/dosing statements, and is specifically preferred to be right after “Dosage and Administrator.”
The Circular directs manufacturers to institute labeling changes for OTC NSAIDs so that these products remain allowed in the market only if required package insert revisions are made.
BFAD instructs selective COX-2 manufacturers (including Celebrex and Arcoxia) to implement additional actions beyond label changes, including monitoring and study commitments.

COX-2 inhibitor label requirements

Manufacturers of selective COX-2 inhibitor drugs must include a black box warning and contraindications addressing both cardiovascular (CV) events and GI risks.
Absolute contraindications for selective COX-2 inhibitors must include patients with a history of: Stroke (Cerebrovascular accident, CVA), Heart attack (Myocardial infarction, MI), Coronary artery bypass graft (CABG), and Congestive heart failure (CHF) NYHA II - IV.
Under the CAUTION/WARNING statement, COX-2 inhibitors must include directions that: they are not to be given to patients with allergy to NSAIDs and those with asthma.
The CAUTION/WARNING statement must further include: exercise caution in patients with ischemic heart disease and risk factors such as hypertension, hyperlipidemia, diabetes, smoking, and peripheral arterial diseases.
The CAUTION/WARNING statement must advise that, considering association between cardiovascular risk and COX-2 inhibitor exposure, doctors are advised to use the lowest effective dose for the shortest duration of treatment.
The CAUTION/WARNING statement must require stopping intake and COX-2 inhibitor treatment upon appearance of skin rash and signs of hypersensitivity.
If not yet instituted, warning statements must include potential gastrointestinal (gastric and liver) and renal toxicities.
The Circular advises manufacturers to implement the following additional actions for Celebrex and Arcoxia:
- include black boxed warning and contraindications about CV and GI risks (referring to Bureau Circular No. 8, s. 2005);
- inform practitioners to use the lowest effective dose for the shortest duration consistent with individual patient treatment objectives;
- commit to conduct a long-term study and monitoring to assess safety; and
- provide Mandatory Patient Leaflet Information.

Prescription and OTC NSAIDs labeling duties

Manufacturers of prescription nonselective NSAIDs must include a boxed warning about potential CV events and potentially serious GI adverse events.
Manufacturers of prescription nonselective NSAIDs must include contraindications for use in Coronary Artery Bypass Graft (CABG) operations.
Prescription nonselective NSAID labeling must instruct patients to discuss with doctors the risks and benefits of NSAIDs and the importance of using the lowest effective dose for the shortest duration possible whenever NSAID treatment is required.
For OTC NSAIDs, the Circular directs continued market allowance provided package insert revisions are instituted, including more specific information about potential CV and GI risks.
OTC NSAID revisions must include stronger warnings limiting dose and duration of treatment according to package instructions.
OTC NSAID revisions must include a warning about potential skin reactions, including instructions to stop treatment once itchiness or rashes occur.
OTC NSAIDs must provide public information through posters in drugstores, and posters and leaflets for these products must be made available in drug outlets.

Mandated OTC poster content

The Circular provides a required poster structure (English and Tagalog) for OTC NSAIDs with suggested contents.
The poster must define what an NSAID is and include examples.
The poster must list side effects and required actions, including: bleeding stomach ulcers, with instructions to stop taking the NSAID when there is burning stomach pain, black bowel movements, or bloody coffee-ground vomiting.
The poster must list potential liver impairment signs including nausea, vomiting, tiredness, loss of appetite, jaundice (yellow coloring of skin and eyes), “flu-like symptoms and dark urine,” with instructions to stop taking the NSAID if these occur.
The poster must list potential kidney problems and instruct users to stop that NSAID if there is worsening of kidney problem.
The poster must warn of fluid retention and swelling, including that fluid retention may be potentially serious if there is high blood pressure or heart failure.
The poster must instruct that NSAIDs should not be taken if the user is allergic to aspirin.
The poster must list when to consult a doctor, including heart problems, high blood pressure, stomach ulcers or stomach bleeding, asthma, allergy to aspirin or other NSAID, and renal problem.
The poster must require consultation with a physician or healthcare professional if pregnant, trying to become pregnant, or breastfeeding.

Annexed contraindications and warning placement

Annex A requires selective COX-2 inhibitor (e.g., celecoxib and etoricoxib) black box warning content to include absolute contraindications for: Stroke (CVA), Heart attack (MI), CABG, and CHF NYHA II - IV.
Annex A directs that the above warning be placed right after “Dosage and Administrator,” preferably in the first page of the insert.
Annex A requires CAUTION/WARNING content covering: allergy to NSAIDs, asthma, caution in ischemic heart disease and specified risk factors, advice to use the lowest effective dose for the shortest duration, stopping upon skin rash/hypersensitivity, and inclusion of potential GI (gastric and liver) and renal toxicities if not already instituted.
Annex B requires prescription NSAID black box warnings to match the same absolute contraindications as COX-2 inhibitors (including Stroke, Heart attack, CABG, and CHF NYHA II - IV) and adds Uncontrolled hypertension.
Annex B directs placing the above warning right after “Dosage and Administration,” preferably in the first page of the insert.
Annex B requires a prescription NSAID warning statement that includes: contraindication in patients with history of hypersensitivity to ASA or any other NSAIDs; contraindication in patients with previous or active peptic ulceration; and caution in patients with cardiac, liver and renal disease, including dose adjustment to the lowest effective dose and monitoring of renal and liver functions.

Deferral and effect

BFAD defers the implementation of PSD Memos 05-2005 and 06-2005.
BFAD directs that revised labeling requirements for selective COX-2 inhibitors and NSAIDs guide manufacturers for compliance through updated package inserts, patient leaflets, and OTC posters as mandated.