Clinical Content Clinical Pharmacology Help
Clinical Pharmacology drug monographs discuss a wide range of prescription, over-the-counter (OTC), investigational, nutritional and herbal products. As is the role of a drug compendium, Clinical Pharmacology only discusses those drugs that have accepted medical/therapeutic utility. Therefore, DEA Schedule I substances (e.g., heroin) are not covered; however, since Cocaine is a FDA-approved prescription drug, it does have recognized and approved uses and is thus discussed in Clinical Pharmacology. All information is based on products and practice within the United States. The information within these monographs is presented in a standardized format to provide the following information:
The exact format of this information may vary throughout program, but these concepts will be addressed throughout all monographs. To ensure the most up to date drug information, the Clinical Pharmacology editorial team updates monograph content in a ”r;real time” format. This allows for tremendous flexibility as well as the ability to be responsive to late breaking medical news, trials and previously unannounced drug label changes. Content updates to the database include new FDA-approved drugs, new non-prescription and herbal therapies, newly published information regarding FDA label changes and relevant clinical studies affecting off-label utilization. For more information regarding Clinical Pharmacology editorial processes, see Editorial Policies.
For older drugs or those not widely available, such as those only available through the Center for Disease Control (CDC), an abbreviated format is followed. These monographs still include information regarding indications, dosage, contraindications/precautions, interactions, and adverse reactions. For drugs available only through special access, information on how to obtain the product is also provided.
Clinical Pharmacology includes discussions regarding drug products in late stage clinical development (undergoing phase III clinical trials or completed NDA submitted to the FDA) or those being reviewed under the FDA ”r;Fast Track” program, when clinical information is available. Information regarding such products is usually limited, especially in terms of adverse reaction, drug interaction, or general precaution information.
References are cited for controversial or less well-known concepts. Off-label uses are generally referenced to the original data -- ideally, a double-blind study from a peer reviewed journal -- when available. Case reports and data from small, uncontrolled studies are cited only when more rigorous, controlled trials are unavailable. Information that is commonly known and readily available in other drug reference books, or, information that is summarized in the manufacturer's product labeling (i.e., the "package insert") is generally not referenced. When appropriate and available, links to the PubMed abstract are provided.
All monographs include a description section that gives a high level overview of the drug product, key development issues, place in therapy, and related regulatory information. Also within this section, you will find classifications, list of US product brand names, and, when available, chemical structures.
Summary of drug mechanism of action and pharmacodynamics.
Summary of the pharmacokinetics of the drug based upon dosage form and method of administration. Includes discussion of absorption, distribution, metabolism, and excretion as well as important considerations for special populations (e.g., pediatrics, elderly, females) and disease states (e.g., hepatic dysfunction, renal dysfunction, etc)
The Administration section outlines administration instructions and warnings for all available dosage forms associated with the drug. In addition to administration information, this section also includes important regarding product preparation information, such as reconstitution and/or dilution instructions and extemporaneous preparations where the formula is well-documented.
The IV Compatibility Pro add-on module offers additional Clinical Pharmaceutics and Extemporaneous Compounding information from the Trissel’s™ 2 Clinical Pharmaceutics Database. If you have access to the IV Pro module, you will find the following additional features within the monograph Administration section:
Clinical Pharmaceutics information regarding parenteral products, including pH, sodium content, sorption/leaching, and maximum stability concentrations.
Clinical Pharmaceutics information regarding over 280 non-parenteral drug ingredients/products, including solubility, pH, and general compatibility information.
Extemporaneous compounding formulations for over 280 non-parenteral drug ingredients for various routes of administration.
The following information will be provided within the Clinical Pharmaceutics section (where applicable):
pH Range - Displays the pH range of the product formulation(s).
Formulation - Presents the composition and concentration(s) and/or content of the most common commercially available dosage forms, including the excipients.
Reconstitution/Preparation - Presents the preparatory steps needed to make the "finished pharmaceutical" ready for actual administration. Reconstitution instructions for dry product injections as well as required dilution instructions for either liquid or dry injections are included in this section.
Sodium Content - Displays the sodium content present in the product(s).
Osmolality/Osmoarity - This category presents the osmolality of the commercial product and/or the osmolality of the product after dilution in common infusion solutions. Osmolality (milliOsmoles per unit mass of solution; i.e. mOsm/kg) is the most common units of osmotic pressure for the injectable drugs in Trissel’s™ 2, while osmolarity (milliOsmoles per unit volume; i.e. mOsm/L) may also be used, especially for large volume parenterals. They are very similar in most cases, but not necessarily identical. An isotonic or iso-osmolar solution is one having the same or nearly the same osmotic pressure as blood such as sodium chloride 0.9%, which has an osmolarity of 308 mOsm/L. Hypotonic and hypertonic solutions are those having a lower or higher osmotic pressure, respectively.
Storage - Presents the manufacturer's recommended storage conditions for the commercial products.
Stability - This section presents summaries of the available stability information for drugs in various packaging configurations and under varying storage conditions. Information on the stability of the reconstituted drug is included (when appropriate) along with the stability upon dilution in infusion solutions, stability when repackaged, particularly in syringes, and other stability information presented with appropriate subheadings. Any special information unique to the stability of the drug appears in this section. Certain common stability factors (i.e. effects of light, frozen storage, sorption to materials) have their own categories and are described below.
pH Effects - A drug's stability information related to solution pH will be included in this category. Both physical and chemical stability of some drugs may be affected by solution pH, and this should be considered in determining drug stability issues when this information is available.
Light Effects - This section presents information on the impact, if any, of exposure to common light sources (florescent, incandescent, daylight, etc.) on the stability of the drug when that information is available.
Freezing - This section presents any information related to the physical and chemical stability of the drug in the frozen state. Freezing of drug solutions to extend stability has been evaluated on a number of drugs, and the information that has been developed along with any manufacturers' recommendations will be presented here.
Filtration - Information on the binding of drugs to filters or the absence of binding to filters is included in this section when available. Some drugs, particularly those used in very low concentrations, may be subject to substantial, clinically meaningful, losses due to binding to filters.
Sorption/Leaching - Information on drug interactions with materials including the loss of drug due to sorption or the leaching of substances from containers and devices will be presented in this section. Sorption refers to the process of drug loss to various container and device materials that the drug contacts. The term "adsorption" refers to the adherence of a drug to the surface of the container or device material. The term "absorption" refers to the loss of drug into the matrix of the container or device material. The generic term "sorption" refers to either or both loss processes. Although sorption is most commonly thought of in the context of loss to plastic bags and infusion tubing, it may occur with a variety of materials, including glass. If losses are sufficiently large, sorption may have an adverse impact on the patient's therapy. Leaching refers to the drug solution extracting one or more components from the container or device material into the solution, which is then delivered into the patient. The most commonly described leaching occurs with the plasticizer diethylhexyl phathalate (DEHP) leached from polyvinyl chloride (PVC) plastic by drugs that contain a surfactant in their formulation. The oily DEHP (which makes PVC soft and pliable) is extracted by the detergent action of the surfactant and is subsequently delivered to the patient. Although this is by far the most common form of leaching, other components of stoppers/closures, syringes plunger tips, and other materials may be leached as well.
Other Information - Miscellaneous information for which there is no specific category is presented here.
Stability Max - This section presents in pointed and abbreviated bullet form the longest stability period(s) identified in the accumulated research to date for the drug in D5W and NS, the most commonly used solutions, and occasionally others as well. The answer to this most commonly asked question is presented for quick and easy reference.
The user should note that not all of these information categories always have information for every drug. However, if information is available, it will be included. When information is present, the category button will have dark lettering and will activate when clicked. If no information is available, the button will be grayed out and nothing will happen if it is clicked.
Extemporaneous Compounding Information
The information on the individual compounded drugs is provided in a number of categories; most are related to intended route of administration. The information included within the Extemporaneous Compounding section are as follows:
Identity/Properties - Information on the nature and properties of the bulk drug and dosage forms is included in this category. In addition to a general description, subheadings may include solubility, pH, pKa, and others.
General Stability Considerations - General information related to stability of the drug is presented in this section.
Drug Compatibility - Information on the compatibility of non-parenteral and compounded preparations with other drug products is included in this category.
Stability Reports of Compounded Preparations - Presented as summaries of the original research reports and are categorized by the intended route of administration. Although this work is not a compounding "cookbook" for formulas, the stability research report summaries do include a description of the compounded product(s) along with the research methods used in the evaluation and the stability results of the study. The most common preparations having stability reports have their own category buttons and include the following:
Enteral feeds
Inhalation/Nasal spray
Injection, extemporaneous
Irrigation
Oral liquid
Oral solid
Oral other form
Rectal
Topical
Other formulation
The user should note that not all of these information categories will have information for every drug. Indeed, most drugs have only one or two types compounded formulations that have been tested for stability. However, if information is available, it will be included. When information is present, the category button will have dark lettering and will activate when clicked. If no information is available, the button will be grayed out and nothing will happen if it is clicked.
This section outlines conditions where the drug can be used as well as the dosing information. Each indication discussion is formatted such that the indication information is presented first, then the route of administration, which may be product specific, and then the dosing information is broken down by patient populations as outlined below.
Adults: 18 - 64 years
Geriatric: 65 years and greater
Adolescents: 13-17 years
Children: 1 - 12 years
Infants: 1 - 11 months (30 - 364 days)
Neonates: 0 - 29 days
Indication terms found in the drop-down menu provides a list of FDA-approved indications as well as ”r;off-label” (non-FDA-approved) indication terms. Clicking on these terms allows you to navigate directly to that topic within the content. Additional links in this drop-down menu include maximum dosage information, and dosing information for patients with hepatic or renal impairment.
While indications terms in Clinical Pharmacology generally conform to standard diagnosis terms, clinicians should realize that only conditions that are treatable with drug therapy are included. Generally, the most specific term is used (e.g., "atrial fibrillation," not "cardiac arrhythmias"). The goal of Clinical Pharmacology is to impart the current clinical perspective on pharmacological treatment: non-FDA-approved indications are included when the use represents current practice and a dosage regimen has been established and documented for the indication. Off-label uses are generally referenced to original clinical research, when such data (evidence) are available. Off-label (i.e., non-FDA-approved) indications are designated by the "†" symbol throughout the program.
Drug interaction discussions included within Clinical Pharmacology monographs include drug-drug, drug-class, drug-herb/nutritional supplement, and drug-lifestyle type interactions. These discussions are based on clinical data and are not limited to those that are only described in the manufacturer's product labeling (i.e., the package insert); all drug interactions are referenced. In some cases, "theoretical" interactions are included when it appears there is sufficient evidence to suggest an interaction might occur between 2 drugs due to pharmacokinetic or pharmacodynamic properties, even though clinical documentation of such an interaction may be lacking. An example of this is when a drug is known to affect a particular hepatic cytochrome P450 (CYP450) isozyme. In this example, other drugs known to be metabolized by that pathway or known to inhibit or induce this pathway are listed as potential interactions.
The drug interaction drop-down index provides a list of drugs that interact with the drug(s) discussed within the monograph. This listing can be sorted alphabetically or by severity of the drug interaction. If the monograph drug(s) interacts with all members of a drug class (i.e., all quinolones), then the drug class is listed within the drug interaction list. If the monograph drug(s) interacts with only some but not all members of a drug class, then only those specific members of the drug class are listed as interacting drugs.
The drug interaction ranking system for Clinical Pharmacology considers many factors, including published drug interaction ranking systems (e.g., Hansten and Horn’s Drug Interactions), QA healthcare specialists, and literature concerning the ranking, identification, and classifications of drug interactions in databases was reviewed (References 1&endash;4, listed below). The ranking system for Clinical Pharmacology is applicable for both healthcare professional drug and consumer drug interactions (i.e., for non-health care professionals) as well as the unique way Clinical Pharmacology deals with the display of drug interactions (i.e., drug-drug direct interactions, and also drug-class interactions, where a drug is known to interact with all drug members of a given pharmacologic class.
Clinical Pharmacology uses a 4-level ranking system adapted from recommendations from an article by Phillip Hansten, John Horn, and Thomas Hazlet (Reference 1). By using a 4-level system, Clinical Pharmacology accurately categorizes interactions into those that are severe, significant or require an intervention [Rank 1 (Severe) or 2 (Major)], those that could be significant in selected circumstances [Rank 3 (Moderate)], or those that rarely caused clinically significant problems [Rank 4 (Minor)]. The ranking system, in conjunction with Clinical Pharmacology editorial philosophy, does not give drug interaction alerts or ranks for drugs known not to interact and instead focuses on actual interactions.
The rank is to be used in conjunction with the written content that provides additional information specific to the interaction. It is very important to not only read the number of the rank, but also the associated content.
References:
1. Hansten PD, Horn JR, Hazlet TK. ORCA: Operational Classification of Drug Interactions. J Am Pharm Assoc 2001;41:161-5.
2. Peterson JF, Bates DW. Preventable medication errors: identifying and eliminating serious drug interactions. J Am Pharm Assoc 2001;41:159-60.
3. Hazlet TK, Lee TA, Hansten PD, Horn JR. Performance of community pharmacy drug interaction software. J Am Pharm Assoc 2001;41:200-4.
4. Hansten PD and Horn JR. The Top 100 Drug Interactions- a Guide to Patient Management, Year 2003; H&H Publications, Edmonds WA, 2003.
Professional Drug interaction severity ratings are defined as follows:
Severe (Level 1) - The use of these medications together is contraindicated or the medications are not usually taken concurrently because the interaction may be life threatening or may cause serious harm. Avoidance of the drug combination is preferred because of the risk: benefit ratio. Refer to the drug interactions comments for rare situations that might be an exception.
Major (Level 2) - These medications may result in the potential deterioration of the patient’s condition from either an increase or decrease in the effect of at least one drug. The patient may need further therapy and/or an alteration in therapy to avoid or limit the potential for interaction. Alternative drug therapy may be preferred in selected cases. The patient should be monitored for the possible manifestations of the interaction. Refer to the drug interactions comments for rare situations that might be an exception.
Moderate (Level 3) - The interaction may be bothersome or unnoticeable with limited clinical effects. Manifestations of the interaction may consist of an increase in the frequency or severity of side effects or decreased effectiveness of a drug but normally would not require a major alteration in therapy. Depending on the clinical situation, the interaction risk may be minimized with selected actions. The patient should be monitored for the possible effects of this interaction. Refer to the drug interactions comments for situations that might be an exception.
Minor (Level 4) - The interaction may be bothersome or unnoticeable with limited clinical effects. Manifestations of the interaction may consist of an increase in the frequency or severity of side effects, or a decrease in the effect of the drug. However, the interaction normally would not require a major alteration in therapy or special precautions. The patient should be monitored for the possible effects of the interaction.
For consumer drug interaction reports, the same 4-level severity rating system as professional version is used. The definition of the severity consumer ranks is provided in a consumer-friendly manner as below:
Severe: Avoid taking these drugs together. (Level 1) - These drug interactions may cause very serious side effects. Do not take these drugs together without contacting your doctor or health care professional for more information. If you MUST continue taking both drugs, be alert. You need to be closely monitored. Report any new or unusual side effects to your health care professional immediately.
High (Level 2) - These interactions commonly result in a change (increase or decrease) in the effect of at least one drug. Your treatment needs to be closely monitored. Report any new or unusual side effects to your health care professional immediately. There may be an alternative to one or both of the medications available; ask your doctor or health care professional if you have questions. If the interaction occurs between an over-the-counter/non-prescription (OTC) drug and a prescribed drug, consult your doctor or pharmacist before taking the OTC drug.
Moderate (Level 3) - These interactions sometimes make a health condition or a drug-related side effect worse. Usually, you can continue to take both drugs, but there may be ways to lower the risk of an interaction. You should report any new or unusual side effects to your health care professional immediately. If the interaction occurs between an over-the-counter/non-prescription (OTC) drug and a prescribed drug, consult your pharmacist before taking the OTC drug.
Low (Level 4) - A slight risk for an interaction exists. The interaction may affect one or both drugs, but rarely causes significant problems. Usually, you can continue to take both drugs, but be sure to report any new or unusual effects to your health care professional.
"Contraindications" are absolute conditions where a drug should not be used. "Precautions" are conditions where a drug can be used, albeit with caution. An absolute contraindication term will appear in italics; precautions appear in plain type. These terms are separated within the Contraindications/Precautions drop-down index.
The definition of the Black Box icon shows within the drop-down for ALL Monographs whether a Black box warning is present or not.
Within the Contraindications/Precautions section of a monograph, "pregnancy" and "breast-feeding" are discussed for ALL drugs. A quick link to just the pregnancy and breast-feeding information is also available so that the user can quickly locate this specific discussion regarding these common concerns for drug usage; the same information is presented in both sections. The discussions include comments regarding FDA pregnancy risk category assignment and additional explanatory data on maternal or fetal risk when helpful. The intent of these enhanced discussions is to describe issues that may not be readily explained by knowing the FDA pregnancy risk category alone.
For "FDA pregnancy risk category X" drugs, pregnancy is considered an absolute contraindication to use. Breast-feeding is italicized when breast-feeding is known to be absolutely contraindicated during the use of the drug based on the manufacturer's label or on the basis of expert consensus.
Because all drug monographs include these precautionary terms, the Multi-Criteria Search feature and Clinical Comparison Report will not provide differentiating information if these terms are used.
Renal impairment is an important precaution for many drugs. Clinical Pharmacology utilizes three distinct terms that address this issue:
Renal Disease: describes any disease involving the kidneys, regardless of the impact on renal function.
Renal Impairment: describes any situation where creatinine clearance is < 90 ml/min. This limit was selected because some drugs (e.g., allopurinol) require dosage adjustment at that point.
Renal Failure: is defined as creatinine clearance < 10 ml/min.
Thus, for some drugs, two, or even all three terms may appear in Contraindication/Precaution terms list.
The adverse reactions listed within the drop-down index for each monograph have been reported in product labeling or have been established clinically for the monograph drug(s). Where possible, the adverse reaction (ADR) incidence rate is provided; however, even this information is limited due to the relatively small or restricted populations usually reported. In many cases, the ADR incidence rates are reported only for a specific dose in a specific patient population being treated for a targeted disease state, therefore limiting the applicability of the information across large, diverse populations and diseases.
In general, adverse reactions are included as standardized terms within the drop-down index in any of the following situations:
From clinical trial data reported in the FDA-approved product labeling, if adverse reaction (ADR) occurred at a higher incidence in patients treated with the drug than in patients treated with placebo (or the control drug) and at least at a rate of 1% within the population tested or is associated with serious morbility/mortality.
Data are available to support a causal relationship between the drug and the ADR
The ADR has been reported during use of the drug and is likely to be drug-related based on knowledge of the pharmacology of the drug and knowledge of adverse reactions reported with other drugs in the same pharmacologic class.
Although adverse events that do not meet the above criteria will not be included as a bulleted term, they may be discussed in the Adverse Reactions section of the monograph.
This section describes the different dosage forms and strengths of US marketed products associated with the drug monograph. Within the How Supplied listing, products are grouped by ingredient, strength, and dosage form. For example, all acetaminophen 650 mg products will be listed together. This listing includes the marketer as well as an indicator if the product is off-market. For more details regarding drug product information included within Clinical Pharmacology, see the Drug Product section.
The monitoring parameter section is intended to guide the health care practitioner to specific patient monitoring required before and during the use of a drug. Monitoring parameters include physical (i.e., ophthalmologic exam, pelvic exam, weight), laboratory (i.e., blood glucose, plasma HIV RNA, urinalysis), radiological (i.e., chest X-ray, thallium stress test), and other specific monitoring tools that the health care practitioner should perform during drug therapy. For appropriate monographs, this section will also include information regarding the therapeutic drug levels.
Detailed monitoring information is included throughout the drug monograph related to dosage, contraindications, precautions, or adverse reactions when applicable.
Within the monograph, IV Compatibility information is presented for all available drugs and solutions in combination with the monograph drug product. The table is sorted by IV Drugs and IV Solutions. IV compatibility information is provided for the monograph drug and other IV drug or solution for admixtures, Y-site administration, and combination within a syringe.
The IV Compatibility link will be provided within a monograph that has an IV formulation, as shown here:
Using warfarin as an example, the IV Compatibility of Warfarin sodium with other IV drugs is illustrated in the image below. Also notice that the results are sorted by IV route: Admixture, Syringe and Y-Site Administration.
Included in these IV Compatibility results, (as you scroll further down on this page), is the IV Solution Compatibility with Warfarin sodium, as illustrated here:
The IV Compatibility List drop down menu (as illustrated below), allows you to navigate quickly to compatibility information regarding the monograph drug and another IV drug or solution.
When viewing the IV Compatibility tables, the compatibility information will be identified in one of the following four ways:
Click here for (Compatible) sample details.
If the study indicates one or more of the following outcomes, the results will be designated as compatible:
No change in visible or electronically-determined particulates, haziness or turbidity, frank precipitation, color, or evolution of gas.
All drug components in the test samples are found to be chemically stable, (<10% loss of intact drug), for at least 24 hours under the conditions being tested.
All drug components in test samples are found to be chemically stable, (<10% loss of intact drug), for the entire study period under the conditions being tested, even if the study period was <24 hours.
NOTE: Some admixtures that lose >10% of the intact drug in 24 hours or are tested for less than 24 hours may be used for lesser time periods.
Click here for (Incompatible) sample details.
If the study indicates one or more of the following outcomes, the results will be designated as incompatible:
A change in visible or electronically-determined (even if not visible) particulates, haziness or turbidity, frank precipitation, color, or gas evolution occurs.
One or more of the drug components in the test samples exhibits a loss of intact drug >10% within 24 hours under the conditions being tested.
Click here for (Results uncertain, variable or dependent on conditions) sample details.
If the study results do not fit conventional compatible or incompatible guidelines, the results are designated as "Results uncertain, variable or dependent on conditions." Judgment will need to be applied when evaluating these results. Examples of such results include:
A transient precipitation formed upon mixing but then disappeared. The precipitate may or may not appear again later.
Among repeat test samples, microparticulate formation was electronically determined to have formed in some samples but not others.
The test drug in a solution was stable in one container type but not another, or with some drug delivery devices but not others.
Compatibility of a drug or drugs is dependent upon the individual manufacturer(s) formulation of the products and/or the use of specific product formulations.
Any other research result that does not fit the conventional guidelines of compatibility or incompatibility.
If the IV Compatibility results indicate that no data is available, then there is no data available within the Trissel’s™ 2 Clinical Parmaceutics Database and/or Trissel’s™ Tables of Physical Compatibility regarding the compatibility of the drugs and/or solutions.
Within the tables, you are able to click
on 
, 
, or 
to display the compatibility
study details.
If there is more than 1 study available, you will see "1 of X" and an arrow to page through the multiple study results, as illustrated here:
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The compatibility report will be grouped by routes; (i.e. Admixture, Syringe, and Y-Site Administration). |
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If you wish to compare multiple drugs, you will find a link to start a multi-drug IV compatibility report in the upper right corner of the screen:
Clicking on this link will allow you to run an IV Compatibility report on multiple drugs. The "Drug List" will be pre-populated with the drug product from the monograph. Click here for a step-by-step instruction on how to create an IV Compatibility report. |
The IV Compatibility Pro add-on module offers more extensive compatibility study information from the Trissel’s™ 2 Clinical Pharmaceutics Database. With this module, the following will be available with the IV Compatibility information:
Detailed information regarding the IV Compatibility study performed including the drug concentrations studied and study parameters such as the analytical method, duration, storage conditions, and the container used, as well as the reference citation.
Chemical stability information provided (where available).
As is illustrated below, this module includes additional links as part of the compatibility details popup window; (i.e. Chemical Stability, Method, Storage Conditions, Container, and Duration). As each link is clicked, the text at the bottom of this window will change accordingly, providing you with greater information and detail about the compatibility study that was performed.
