Discussions that mention valium

Pain Management board

Hey Phlox, The 15% or 20% increase caused by P450 manipulation was proportianately enough to make a difference pain wise, in what I experienced. In many cases, say a Soma or a valium was 15% stronger or weaker, you may not notice or atribute it to some interaction, however there are some meds that could cause great problems if levels can't be assured or P450 inhibits or increases serum level.


Generic substitution for drugs has become a widespread practice as the Food and Drug Administration (FDA) approves bioequivalent drugs, and patients and payors seek ways to trim healthcare costs. Formulation substitution (FS) can include proprietary to generic, one generic to another or generic to proprietary. In many cases, FS poses no problem to the health of the patient. Concerns have been raised, however, that uncontrolled use of such substitution may indeed be harmful in certain cases. For the physician with cardiovascular patients, the greatest concern relates to the safety and efficacy of such substitutions in antiarrhythmic and anticoagulation treatment. Drugs used in these treatments often have a narrow therapeutic index (NTI), defined as the range of concentrations above which efficacy is seen and below which toxicity is avoided. NTI increases the chances of adverse clinical consequences including arrhythmia recurrence, proarrhythmia and death.

It is critical that physicians have a better understanding of generic drugs, how they are tested and the true comparative value of FS to better treat patients and avoid any possible adverse consequences. This was made very clear when a 1997 questionnaire to assess attitudes, beliefs, knowledge and experiences with generic drugs and generic substitution was sent to 3,639 physicians nationwide. Cluster analysis was used to identify attitudinal groups that were then analyzed with respect to differences in beliefs, knowledge, and experience with generic drugs. Perceptions of the therapeutic index for 15 branded drugs and comfort in substituting those products with generic alternatives were assessed. Only 17 percent of physicians could correctly identify the FDA standards for bioequivalency. (1)

It is necessary to further consider issues of patient compliance in the issue of FS. Without adequate information, patients are apt to make medication errors, especially over time as memory of oral instructions fades. And when substitutions are made from refill to refill, the patient may become confused and continue to take one drug from a past prescription while beginning use of a substitution without realization that they are prescribed for the same treatment. Consumers need to be better informed about FS, medication instructions and risk factors. Patient package inserts may be the most effective way to enhance safety for patients who risk overlapping similar drugs.

FDA Guidelines for Approval of FS

According to FDA regulations, a generic copy of a reference drug must contain identical amounts of the same active drug ingredient in the same dosage form and route of administration and meet compendial or other applicable standards for strength, purity, quality and identity. “Inactive ingredients” such as binders and fillers are allowed to differ but must occur in a ratio to the active compound similar to that of the reference drug. It is assumed that these “inactive ingredients” will not alter the performance of the product. However, since these ingredients may contain lactose or gluten products, they could change gut motility and drug absorption in sensitive patients.

For immediate-release solid oral formulations, testing protocol is typically a randomized, single-dose, crossover design conducted after an overnight fast, for which half of the subjects initially receive the innovator (original) product. After a sufficient period, subjects are crossed over to receive the generic formulation. The remaining subjects receive the two drug products in the reverse order with a suitable washout period between dosing sessions. After administration of each drug product, several blood samples are collected, ordinarily for approximately 4 to 5 half-lives of the drug, to enable adequate characterization of the drug's concentration time profile.

Approval of a generic version of a proprietary drug by the FDA requires demonstration of “chemical equivalence” (similar quantities and availability of the active ingredient in proprietary and generic formulations), and “bioequivalence” (defined by absorption parameters generally falling between 80% and 125% of those obtained with the proprietary agent under the same testing conditions) (2) The use of the –20%/+25% rule is based on a regulatory decision that for most drugs that difference in concentration of the active ingredient in blood will not be clinically significant.

Concern Over FS for NTI Drugs

Drugs with a narrow therapeutic range, or index, (NTI) cause the greatest concern for many physicians. Under Section 320.33(c) of Code of Federal Register 21, the US FDA defines a drug product as having a narrow therapeutic ratio as follows:

1.There is less than a two-fold difference in median lethal dose and median effective dose values, or
2.there is less than a two-fold difference in the minimum toxic concentrations and minimum effective concentrations in the blood, and
3. safe and effective use of the drug products require careful titration and patient monitoring.

In general terms, NTI drugs are those “for which a relatively small change in systemic concentrations can lead to marked changes in pharmacodynamic response” (3)

The National Kidney Foundation published a white paper in 1999 (4) raising inequivalence concerns for transplant organ immunosuppressants and introduced the term “critical-dose drug” to define drugs that:

1. Have a narrow therapeutic range.
2. Require blood level monitoring.
3. Are administered in doses based on body weight or other highly individualized dosing requirements.
4. Have serious clinical consequences if overdosing or underdosing occurs.
5. Manifest steep dose response relationships for efficacy, toxicity, or both.
The authors considered both cyclosporine and tacrolimus to be critical-dose drugs.

Sorry, I got tired and did the cut and paste thing. Take care, Dave