Warning Deficiencies

Most warnings that are currently (2008) applicable suffer from some deficiencies. These include 

The underlying toxicology used as the basis for warnings is based on the effects on healthy adults. The effects on children or on those with preexisting medical conditions are largely ignored. 

The warnings largely ignore the effects of mixtures. Warning information is supplied almost exclusively for the individual chemicals only. 

In the United States toxic chemicals in products are only required to be listed if they are present in concentrations of 1.0% or more (or 0.1% or more, if carcinogenic). Accordingly, plastic products that are often used in surgery and in baby formula bottles are not required to warn that they contain endocrine disrupting chemicals, which are hazardous at concentrations far less than 1% (see Chapter 22). 

Long-term testing is not required prior to dissemination warnings. Only short-term laboratory animal tests are frequently carried out. 

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Specific concomitant medications or consumptions (check specific statin package insert for warnings) fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat Acquired Immune Deficiency Syndrome, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart per day), and alcohol abuse (independently predisposes to myopathy)... 

After inspection, the inspector prepares a detailed Establishment Inspection Report (EIR). This is the FDA s primary record for the inspection. Time is given to the manufacturer to respond to the deficiencies found and recorded on Form FDA-483. Failure to comply with satisfactory resolution of the deficiencies found will result in the FDA sending out a Warning Letter notifying the manufacturer to comply. If the manufacturer is unable to resolve the deficiency after the deadline set by the FDA, the FDA may proceed to prosecute the manufacturer with an injunction. The injunction is a court order called Consent Decree, and the manufacturer may be required to cease operations until the problem is rectified (see Exhibit 10.4). 

Regulatory authorities inspect GMP facilities to ensure compliance to GMP. The FDA carries out surveillance and compliance inspections. A system-based approach is adopted quality, facilities and equipment, materials, production, packaging and labeling, and laboratory control. Deficiencies are reported on Form FDA-483, which may lead to a warning letter and consent decree if unresolved. 

Atmospheres deficient in oxygen do not provide adequate warning. 

Propane is odorless, and atmospheres deficient in oxygen do not provide adequate warning. ... 

Ora/. Anticoagulant-induced prothrombin deficiency (see Warnings) hypoprothrombinemia secondary to salicylates or antibacterial therapy hypoprothrombinemia secondary to obstructive jaundice and biliary fistulas, but only if bile salts are administered concomitantly with phytonadione. 

WARNING Anaphylactic Rxns w/ use use only if oral Fe not possible administer where resuscitation techniques available Uses Fe deficiency when cannot supl PO Action Fe supl Dose Adul. Iron defic anemia Estimate Fe deficiency, give 25-100 mg IM/IV /d until total dose total dose (mL) = [-.0442 x (desired Hgb - observed Hgb) x LBW] + (0.26 x LBW) Iron replacement, blood loss Total dose (mg) = blood loss (mL) x Hct (as decimal fraction) max 100 mg/d Peds >4 mo. As for adults max 0.5 mL (wt <5 kg), 1 mL (5-10 kg), 2 mL (>10 kg) p dose IM or direct IV Caution [C, M] Contra Anemia w/o Fe deficiency. Disp Inj SE Anaphylaxis, flushing, dizziness, inj site inf Rxns, metallic taste Interactions X Effects W/ chloramphenicol, X absorption of oral Fe EMS Anaphylactic Rxns common taking oral Fe t risk of tox and SEs OD May cause N/V, HA, muscle/joint pain and fev symptomatic and supportive Iron Sucrose (Venofer) [Iron Supplement] Uses Fe deficiency anemia w/ chronic HD in those receiving erythropoietin Actions Fe r lacement. Dose 5 mL (100 mg) IV on dialysis, 1 mL (20 mg)/min max Caution [C, M] Contra Anemia w/o Fe deficiency Disp Inj SE Anaphylaxis, -1- BP, cramps, N/V/D, HA Interactions i Absorption OF oral Fe supls EMS See Iron Dextran OD See Iron Dextran... 

At the conclusion of each inspection, FDA investigators prepare a report summarizing any deficiencies. In cases where they observe numerous or serious deviations, such as falsification of data, DSI classifies the inspection as official action indicated and sends a warning letter or Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) to the clinical investigator, specifying the deviations that were found. 

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