Savvy Psychopharmacology

Two months ago, Mr. P, age 20, experienced paranoid thoughts, anxiety, agitation, and auditory hallucinations. During a brief hospitalization 1 month later, he received IM haloperidol, 2 mg, which he said “made his neck stiff.” After he was discharged, Mr. P, who is White, stopped taking his antipsychotics. During a recent outpatient evaluation, the clinician gives Mr. P a working diagnosis of schizophrenia and prescribes risperidone, 2 mg/d, with plans to titrate to 4 mg/d in the next 2 weeks. However, a week later, Mr. P complains of extreme sedation and feeling “knocked out” and does not want to continue taking the medication. Physical exam reveals slight cogwheel rigidity. His delusional thought content is not improved. The treating physician considers ordering a genetic test to determine Mr. P’s cytochrome P450 (CYP) 2D6 metabolizer status.

Studies investigating relationships among genetic variants thought to impact pharmacokinetics and pharmacodynamics of psychotropic medications have had mixed results.¹ Metabolism of most antipsychotics depends on the CYP450 enzyme system, which is expressed predominantly in the liver (Table 1). CYP2D6 is one of these enzymes and may be responsible for metabolizing approximately 20% to 50% of all medications, including a number of antipsychotics.² Genetic variations of CYP2D6 are common and the frequencies of these variants differ among racial groups.³

The half-life and other pharmacokinetic parameters of an antipsychotic metabolized by CYP2D6 may differ based on whether someone is a poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), or ultrarapid metabolizer (UM).⁴ Regarding CYP2D6 metabolism among Whites, 3% to 5% are UMs, 70% to 80% are EMs, 10% to 17% are IMs, and 5% to 10% are PMs.⁵ By contrast, the percentage of PMs and UMs in the Asian population is low—about 1% for each phenotype; the IM phenotype is more common (65% to 70% in the Chinese population).^5,6 The percentage of PMs in African Americans is roughly 2% to 6%.²

The clinical effect of altered metabolizer status depends on the extent the metabolism of a given agent is dependent on CYP2D6. PM status results in an approximately 2- to 6-fold increase in elimination half-life and overall exposure of aripiprazole,⁷ risperidone,⁸ and iloperidone⁹ (Figure). On the other end of the spectrum are UMs. Because of gene duplication, patients who fall into this category have enhanced metabolic activity. As a result, the therapeutic effect of several medications may be decreased because of faster clearance from the body, leading some physicians to label them as treatment-resistant.

Because side effects of many antipsychotics are dose-dependent, genotyping may be valuable for patients taking agents that are primarily metabolized by CYP2D6.¹⁰ Clinicians now have access to laboratory resources and FDA-approved methods for assessing CYP2D6 gene variants.¹¹ It is debatable, however, whether this testing—which is expensive (≥$400) and may not be covered by health insurance—improves patient outcomes. In Mr. P’s case, if he had been genotyped as a CYP2D6 PM before treatment, his physicians might not have prescribed haloperidol and could have prevented a mild dystonic reaction. Also, they could have lowered the initial risperidone dose or chosen an antipsychotic such as ziprasidone, paliperidone, or quetiapine where the pharmacokinetic consequences of 2D6 poor metabolism are not as severe. Theoretically, one may argue that this could have reduced the risk for antipsychotic-associated side effects that now are a barrier to Mr. P’s desire to continue antipsychotics. On the other hand one may also reasonably argue that there may be other/additional reasons (genetic or non-genetic) that make some patients more sensitive to the side effects of antipsychotics and that simply assessing CYP2D6 status is not enough to guide drug selection and dosing.

Table 1

Cytochrome P450 (CYP) metabolism of commonly used antipsychotics*

Figure: Effects of CYP2D6 poor metabolizer status on the half-life of risperidone, aripiprazole, and iloperidone

EM: extensive metabolizer; PM: poor metabolizer
Source: References 7-9

Use in clinical practice

Proposed expert guidelines recommend halving the normal target dose of risperidone and avoiding haloperidol and phenothiazine antipsychotics in CYP2D6 PMs.¹² These guidelines are based on expert review of the pharmacokinetic effects of CYP2D6 PM status as well as case reports and studies associating CYP2D6 with poor outcomes, usually side effects. Although these studies suggest that determining metabolizer status may be clinically important, many other studies—some very large—have not found evidence for associations between drug metabolizing enzyme variants and clinical outcomes from antipsychotics.¹³

There are 2 clinical scenarios in which one may consider obtaining CYP2D6 genotype information:

• before initiating treatment (Table 2)
• after trying ≥1 agent primarily dependent on CYP2D6 with evidence of dose-related side effect (Table 3).

Identifying PMs could influence drug selection and dosing if this information is available before antipsychotic exposure. Studies have found evidence that CYP2D6 PMs may be at greater risk of experiencing adverse reactions to risperidone compared with other metabolizer groups.¹⁴ Also, prescribing information for aripiprazole and iloperidone recommends halving the dose of these drugs in the presence of CYP2D6 inhibitors, a condition that pharmacokinetically mimics PM status.

Knowing genotype information after ≥1 drugs have been tried may not be as useful. Clinicians often base drug switches or dose titrations on a patient’s experience with present or past doses of the antipsychotic. Examples include slowing titrations or reducing a target dose when a patient, such as Mr. P, experiences side effects, or selecting non-2D6 substrate agents after detecting a pattern of drug sensitivity.

Table 2

CYP2D6 testing before initiating antipsychotics: Benefits vs drawbacks

Table 3

Genotype testing after a patient experiences side effects

Better patient outcomes?

It is not known if obtaining genotype information will provide better outcomes than a “trial and error” approach. Currently, obtaining genotype information before antipsychotic treatment is not standard clinical practice. Because this testing is expensive and requires prior approval from third party payers or out-of-pocket financial resources, testing is not recommended for all patients at this time.

However, a growing body of evidence suggests that knowing metabolizer status could be useful in drug selection or dosing for antipsychotics. This scientific knowledge continues to accumulate, and CYP2D6 genotyping may some day be integrated into routine clinical care. Currently, for patients and physicians with the resources to obtain and the ability to appropriately interpret the test results, this information may prove useful on an individual basis. However, additional studies are needed to support better outcomes from dosing and drug selection based on CYP2D6 genotype information.

Related Resources

• Evaluation of Genomic Applications in Practice and Prevention (EGAPP). www.egappreviews.org.
• Pharmacogenomics Knowledge Base. www.pharmgkb.org.
• Indiana University School of Medicine. P450 drug interaction table. http://medicine.iupui.edu/clinpharm/ddis/table.asp.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone • Geodon

Disclosures

Dr. Bishop receives grant/research support from the National Institute of Mental Health, NARSAD, and Ortho-McNeil-Janssen and has received honoraria from Eli Lilly and Company.

Ms. Chae reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Two months ago, Mr. P, age 20, experienced paranoid thoughts, anxiety, agitation, and auditory hallucinations. During a brief hospitalization 1 month later, he received IM haloperidol, 2 mg, which he said “made his neck stiff.” After he was discharged, Mr. P, who is White, stopped taking his antipsychotics. During a recent outpatient evaluation, the clinician gives Mr. P a working diagnosis of schizophrenia and prescribes risperidone, 2 mg/d, with plans to titrate to 4 mg/d in the next 2 weeks. However, a week later, Mr. P complains of extreme sedation and feeling “knocked out” and does not want to continue taking the medication. Physical exam reveals slight cogwheel rigidity. His delusional thought content is not improved. The treating physician considers ordering a genetic test to determine Mr. P’s cytochrome P450 (CYP) 2D6 metabolizer status.

Studies investigating relationships among genetic variants thought to impact pharmacokinetics and pharmacodynamics of psychotropic medications have had mixed results.¹ Metabolism of most antipsychotics depends on the CYP450 enzyme system, which is expressed predominantly in the liver (Table 1). CYP2D6 is one of these enzymes and may be responsible for metabolizing approximately 20% to 50% of all medications, including a number of antipsychotics.² Genetic variations of CYP2D6 are common and the frequencies of these variants differ among racial groups.³

The half-life and other pharmacokinetic parameters of an antipsychotic metabolized by CYP2D6 may differ based on whether someone is a poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), or ultrarapid metabolizer (UM).⁴ Regarding CYP2D6 metabolism among Whites, 3% to 5% are UMs, 70% to 80% are EMs, 10% to 17% are IMs, and 5% to 10% are PMs.⁵ By contrast, the percentage of PMs and UMs in the Asian population is low—about 1% for each phenotype; the IM phenotype is more common (65% to 70% in the Chinese population).^5,6 The percentage of PMs in African Americans is roughly 2% to 6%.²

The clinical effect of altered metabolizer status depends on the extent the metabolism of a given agent is dependent on CYP2D6. PM status results in an approximately 2- to 6-fold increase in elimination half-life and overall exposure of aripiprazole,⁷ risperidone,⁸ and iloperidone⁹ (Figure). On the other end of the spectrum are UMs. Because of gene duplication, patients who fall into this category have enhanced metabolic activity. As a result, the therapeutic effect of several medications may be decreased because of faster clearance from the body, leading some physicians to label them as treatment-resistant.

Because side effects of many antipsychotics are dose-dependent, genotyping may be valuable for patients taking agents that are primarily metabolized by CYP2D6.¹⁰ Clinicians now have access to laboratory resources and FDA-approved methods for assessing CYP2D6 gene variants.¹¹ It is debatable, however, whether this testing—which is expensive (≥$400) and may not be covered by health insurance—improves patient outcomes. In Mr. P’s case, if he had been genotyped as a CYP2D6 PM before treatment, his physicians might not have prescribed haloperidol and could have prevented a mild dystonic reaction. Also, they could have lowered the initial risperidone dose or chosen an antipsychotic such as ziprasidone, paliperidone, or quetiapine where the pharmacokinetic consequences of 2D6 poor metabolism are not as severe. Theoretically, one may argue that this could have reduced the risk for antipsychotic-associated side effects that now are a barrier to Mr. P’s desire to continue antipsychotics. On the other hand one may also reasonably argue that there may be other/additional reasons (genetic or non-genetic) that make some patients more sensitive to the side effects of antipsychotics and that simply assessing CYP2D6 status is not enough to guide drug selection and dosing.

Table 1

Cytochrome P450 (CYP) metabolism of commonly used antipsychotics*

Figure: Effects of CYP2D6 poor metabolizer status on the half-life of risperidone, aripiprazole, and iloperidone

EM: extensive metabolizer; PM: poor metabolizer
Source: References 7-9

Use in clinical practice

Proposed expert guidelines recommend halving the normal target dose of risperidone and avoiding haloperidol and phenothiazine antipsychotics in CYP2D6 PMs.¹² These guidelines are based on expert review of the pharmacokinetic effects of CYP2D6 PM status as well as case reports and studies associating CYP2D6 with poor outcomes, usually side effects. Although these studies suggest that determining metabolizer status may be clinically important, many other studies—some very large—have not found evidence for associations between drug metabolizing enzyme variants and clinical outcomes from antipsychotics.¹³

There are 2 clinical scenarios in which one may consider obtaining CYP2D6 genotype information:

• before initiating treatment (Table 2)
• after trying ≥1 agent primarily dependent on CYP2D6 with evidence of dose-related side effect (Table 3).

Identifying PMs could influence drug selection and dosing if this information is available before antipsychotic exposure. Studies have found evidence that CYP2D6 PMs may be at greater risk of experiencing adverse reactions to risperidone compared with other metabolizer groups.¹⁴ Also, prescribing information for aripiprazole and iloperidone recommends halving the dose of these drugs in the presence of CYP2D6 inhibitors, a condition that pharmacokinetically mimics PM status.

Knowing genotype information after ≥1 drugs have been tried may not be as useful. Clinicians often base drug switches or dose titrations on a patient’s experience with present or past doses of the antipsychotic. Examples include slowing titrations or reducing a target dose when a patient, such as Mr. P, experiences side effects, or selecting non-2D6 substrate agents after detecting a pattern of drug sensitivity.

Table 2

CYP2D6 testing before initiating antipsychotics: Benefits vs drawbacks

Table 3

Genotype testing after a patient experiences side effects

Better patient outcomes?

It is not known if obtaining genotype information will provide better outcomes than a “trial and error” approach. Currently, obtaining genotype information before antipsychotic treatment is not standard clinical practice. Because this testing is expensive and requires prior approval from third party payers or out-of-pocket financial resources, testing is not recommended for all patients at this time.

However, a growing body of evidence suggests that knowing metabolizer status could be useful in drug selection or dosing for antipsychotics. This scientific knowledge continues to accumulate, and CYP2D6 genotyping may some day be integrated into routine clinical care. Currently, for patients and physicians with the resources to obtain and the ability to appropriately interpret the test results, this information may prove useful on an individual basis. However, additional studies are needed to support better outcomes from dosing and drug selection based on CYP2D6 genotype information.

Related Resources

• Evaluation of Genomic Applications in Practice and Prevention (EGAPP). www.egappreviews.org.
• Pharmacogenomics Knowledge Base. www.pharmgkb.org.
• Indiana University School of Medicine. P450 drug interaction table. http://medicine.iupui.edu/clinpharm/ddis/table.asp.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone • Geodon

Disclosures

Dr. Bishop receives grant/research support from the National Institute of Mental Health, NARSAD, and Ortho-McNeil-Janssen and has received honoraria from Eli Lilly and Company.

Ms. Chae reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Two months ago, Mr. P, age 20, experienced paranoid thoughts, anxiety, agitation, and auditory hallucinations. During a brief hospitalization 1 month later, he received IM haloperidol, 2 mg, which he said “made his neck stiff.” After he was discharged, Mr. P, who is White, stopped taking his antipsychotics. During a recent outpatient evaluation, the clinician gives Mr. P a working diagnosis of schizophrenia and prescribes risperidone, 2 mg/d, with plans to titrate to 4 mg/d in the next 2 weeks. However, a week later, Mr. P complains of extreme sedation and feeling “knocked out” and does not want to continue taking the medication. Physical exam reveals slight cogwheel rigidity. His delusional thought content is not improved. The treating physician considers ordering a genetic test to determine Mr. P’s cytochrome P450 (CYP) 2D6 metabolizer status.

Studies investigating relationships among genetic variants thought to impact pharmacokinetics and pharmacodynamics of psychotropic medications have had mixed results.¹ Metabolism of most antipsychotics depends on the CYP450 enzyme system, which is expressed predominantly in the liver (Table 1). CYP2D6 is one of these enzymes and may be responsible for metabolizing approximately 20% to 50% of all medications, including a number of antipsychotics.² Genetic variations of CYP2D6 are common and the frequencies of these variants differ among racial groups.³

The half-life and other pharmacokinetic parameters of an antipsychotic metabolized by CYP2D6 may differ based on whether someone is a poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), or ultrarapid metabolizer (UM).⁴ Regarding CYP2D6 metabolism among Whites, 3% to 5% are UMs, 70% to 80% are EMs, 10% to 17% are IMs, and 5% to 10% are PMs.⁵ By contrast, the percentage of PMs and UMs in the Asian population is low—about 1% for each phenotype; the IM phenotype is more common (65% to 70% in the Chinese population).^5,6 The percentage of PMs in African Americans is roughly 2% to 6%.²

The clinical effect of altered metabolizer status depends on the extent the metabolism of a given agent is dependent on CYP2D6. PM status results in an approximately 2- to 6-fold increase in elimination half-life and overall exposure of aripiprazole,⁷ risperidone,⁸ and iloperidone⁹ (Figure). On the other end of the spectrum are UMs. Because of gene duplication, patients who fall into this category have enhanced metabolic activity. As a result, the therapeutic effect of several medications may be decreased because of faster clearance from the body, leading some physicians to label them as treatment-resistant.

Because side effects of many antipsychotics are dose-dependent, genotyping may be valuable for patients taking agents that are primarily metabolized by CYP2D6.¹⁰ Clinicians now have access to laboratory resources and FDA-approved methods for assessing CYP2D6 gene variants.¹¹ It is debatable, however, whether this testing—which is expensive (≥$400) and may not be covered by health insurance—improves patient outcomes. In Mr. P’s case, if he had been genotyped as a CYP2D6 PM before treatment, his physicians might not have prescribed haloperidol and could have prevented a mild dystonic reaction. Also, they could have lowered the initial risperidone dose or chosen an antipsychotic such as ziprasidone, paliperidone, or quetiapine where the pharmacokinetic consequences of 2D6 poor metabolism are not as severe. Theoretically, one may argue that this could have reduced the risk for antipsychotic-associated side effects that now are a barrier to Mr. P’s desire to continue antipsychotics. On the other hand one may also reasonably argue that there may be other/additional reasons (genetic or non-genetic) that make some patients more sensitive to the side effects of antipsychotics and that simply assessing CYP2D6 status is not enough to guide drug selection and dosing.

Table 1

Cytochrome P450 (CYP) metabolism of commonly used antipsychotics*

Figure: Effects of CYP2D6 poor metabolizer status on the half-life of risperidone, aripiprazole, and iloperidone

EM: extensive metabolizer; PM: poor metabolizer
Source: References 7-9

Use in clinical practice

Proposed expert guidelines recommend halving the normal target dose of risperidone and avoiding haloperidol and phenothiazine antipsychotics in CYP2D6 PMs.¹² These guidelines are based on expert review of the pharmacokinetic effects of CYP2D6 PM status as well as case reports and studies associating CYP2D6 with poor outcomes, usually side effects. Although these studies suggest that determining metabolizer status may be clinically important, many other studies—some very large—have not found evidence for associations between drug metabolizing enzyme variants and clinical outcomes from antipsychotics.¹³

There are 2 clinical scenarios in which one may consider obtaining CYP2D6 genotype information:

• before initiating treatment (Table 2)
• after trying ≥1 agent primarily dependent on CYP2D6 with evidence of dose-related side effect (Table 3).

Identifying PMs could influence drug selection and dosing if this information is available before antipsychotic exposure. Studies have found evidence that CYP2D6 PMs may be at greater risk of experiencing adverse reactions to risperidone compared with other metabolizer groups.¹⁴ Also, prescribing information for aripiprazole and iloperidone recommends halving the dose of these drugs in the presence of CYP2D6 inhibitors, a condition that pharmacokinetically mimics PM status.

Knowing genotype information after ≥1 drugs have been tried may not be as useful. Clinicians often base drug switches or dose titrations on a patient’s experience with present or past doses of the antipsychotic. Examples include slowing titrations or reducing a target dose when a patient, such as Mr. P, experiences side effects, or selecting non-2D6 substrate agents after detecting a pattern of drug sensitivity.

Table 2

CYP2D6 testing before initiating antipsychotics: Benefits vs drawbacks

Table 3

Genotype testing after a patient experiences side effects

Better patient outcomes?

It is not known if obtaining genotype information will provide better outcomes than a “trial and error” approach. Currently, obtaining genotype information before antipsychotic treatment is not standard clinical practice. Because this testing is expensive and requires prior approval from third party payers or out-of-pocket financial resources, testing is not recommended for all patients at this time.

However, a growing body of evidence suggests that knowing metabolizer status could be useful in drug selection or dosing for antipsychotics. This scientific knowledge continues to accumulate, and CYP2D6 genotyping may some day be integrated into routine clinical care. Currently, for patients and physicians with the resources to obtain and the ability to appropriately interpret the test results, this information may prove useful on an individual basis. However, additional studies are needed to support better outcomes from dosing and drug selection based on CYP2D6 genotype information.

Related Resources

• Evaluation of Genomic Applications in Practice and Prevention (EGAPP). www.egappreviews.org.
• Pharmacogenomics Knowledge Base. www.pharmgkb.org.
• Indiana University School of Medicine. P450 drug interaction table. http://medicine.iupui.edu/clinpharm/ddis/table.asp.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Olanzapine • Zyprexa
• Paliperidone • Invega
• Perphenazine • Trilafon
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone • Geodon

Disclosures

Dr. Bishop receives grant/research support from the National Institute of Mental Health, NARSAD, and Ortho-McNeil-Janssen and has received honoraria from Eli Lilly and Company.

Ms. Chae reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Mr. X, age 47, suffers from major depressive disorder, which he developed 1 year ago after experiencing a myocardial infarction. At that time, Mr. X received brand-name fluoxetine (Prozac), 20 mg/d. After 4 weeks, his mood improved, but he experienced delayed ejaculation, which resolved spontaneously after 12 weeks of treatment.

Because Mr. X recently lost his job and health insurance, he inquires about lowering his health care costs. Discontinuing fluoxetine is not advised, so you recommend changing to a generic formulation. Mr. X tolerates this conversion without difficulty; however, 9 months later he reports he is experiencing delayed ejaculation again. He has had no changes in medical history and has not started any new medications. Mr. X claims he has been compliant with his medication, although he mentions that the fluoxetine tablets looked different when he refilled his prescription 2 weeks ago. You call the pharmacy and discover that they started dispensing generic fluoxetine from a different manufacturer around the time Mr. X refilled his prescription. You prescribe Mr. X his old version of generic fluoxetine, and his sexual dysfunction resolves within 2 weeks.

In the United States, 2.6 billion prescriptions—approximately 70% of all prescriptions—are filled using generic versions of brand-name products.¹ For most patients, generic substitution is acceptable and reduces costs. Although the practice has become routine, certain circumstances may make switching to a generic medication or between generic medication problematic. To understand why, it is important to discuss the FDA’s generic drug approval process.²

Bioequivalence

Pharmaceutical manufacturers developing a generic drug must create a product that will deliver the same amount of medication at the same rate and in the same form (ie, tablet, capsule, suspension, etc.) as the brand-name product. The FDA requires bioequivalence (BE) studies.² These studies usually include fewer than 40 healthy individuals and must show that the generic product has the same pharmacokinetic profile as the brand-name drug (the active ingredient already has been shown to be safe and effective). The generic product can deviate from the brand product’s profile by a set amount—currently a 90% confidence interval limit of 80% to 125%.² This means that pharmacokinetic parameters such as max concentration (Cmax), time to max concentration (Tmax), mean absorption time, and area under the curve (AUC)—which is a measure of overall drug exposure—are no less than 80% and no more than 125% of the parameters seen with the brand-name product. This may seem like a large deviation, but the FDA reports that generally “small differences in blood levels—<4%—may exist in some cases between a brand and its generic equivalent.”¹

A new generic formulation does not have to be tested against other generic formulations, only against the brand-name drug. Therefore, 2 generic formulations may differ pharmacokinetically by more than a 4% difference if one product is on the low side of the BE limit and the other is on the high side. If a patient starts 1 generic and then switches to another, efficacy may be lost or side effects may emerge because of BE differences. In Mr. X’s case, it is possible that the new generic version of fluoxetine resulted in higher plasma drug levels that lead to recurrence of sexual dysfunction.

Exceptions

Generic medications are not recommended for certain medical conditions, such as epilepsy and some hormone replacement therapy, because of lack of satisfactory BE to the brand-name drug.³ For these conditions, generic medications may be used, but should not be substituted for the brand-name product without careful monitoring. Additionally, switching between different generic manufacturers should be avoided.

If you have a question about generic substitution, consult the FDA’s Approved drug products with therapeutic equivalence evaluations⁴—also known as the “Orange Book,” which is available online (see Related Resources). This resource provides guidance about which drugs are interchangeable. The Orange Book is the “gold standard” on approved drug products and their interchangeability.

The Table lists certain psychiatric medications that may have issues with generic substitutions. Most pharmacies stock and dispense only generic drugs that the FDA considers bioequivalent to the brand-name product.

Allergic reactions may occur because of different inert ingredients within each generic or brand-name drug. Generic drug manufacturers are not required to use the same inactive or “filler” ingredients. Some patients may be allergic to 1 version and may require a specific brand or generic version to overcome this potential allergy.³

Although most generic substitutions occur without incident, consider BE differences among products and your patient’s medical condition before initiating a switch. When switching between generics, carefully monitor your patient as you would when switching from the brand-name product to a generic. If new treatment-related issues arise or lack of efficacy occurs, ask your patient if the pharmacy switched to a new generic formulation.

Table

Bioequivalence among generic psychotropics: What to know before you switch

Related resources

• Food and Drug Administration. www.fda.gov/Drugs/default.htm.
• Generic Pharmaceutical Association. www.gphaonline.org.
• Food and Drug Administration. Orange book: approved drug products with therapeutic equivalence evaluations. www.accessdata.fda.gov/scripts/cder/ob/default.cfm.

Drug brand names

• Amitriptyline/Perphenazine • Triavil
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Venlafaxine • Effexor

Disclosure

Dr. Ellingrod is a member of an advisory board for Eli Lilly and Company.

Mr. X, age 47, suffers from major depressive disorder, which he developed 1 year ago after experiencing a myocardial infarction. At that time, Mr. X received brand-name fluoxetine (Prozac), 20 mg/d. After 4 weeks, his mood improved, but he experienced delayed ejaculation, which resolved spontaneously after 12 weeks of treatment.

Because Mr. X recently lost his job and health insurance, he inquires about lowering his health care costs. Discontinuing fluoxetine is not advised, so you recommend changing to a generic formulation. Mr. X tolerates this conversion without difficulty; however, 9 months later he reports he is experiencing delayed ejaculation again. He has had no changes in medical history and has not started any new medications. Mr. X claims he has been compliant with his medication, although he mentions that the fluoxetine tablets looked different when he refilled his prescription 2 weeks ago. You call the pharmacy and discover that they started dispensing generic fluoxetine from a different manufacturer around the time Mr. X refilled his prescription. You prescribe Mr. X his old version of generic fluoxetine, and his sexual dysfunction resolves within 2 weeks.

In the United States, 2.6 billion prescriptions—approximately 70% of all prescriptions—are filled using generic versions of brand-name products.¹ For most patients, generic substitution is acceptable and reduces costs. Although the practice has become routine, certain circumstances may make switching to a generic medication or between generic medication problematic. To understand why, it is important to discuss the FDA’s generic drug approval process.²

Bioequivalence

Pharmaceutical manufacturers developing a generic drug must create a product that will deliver the same amount of medication at the same rate and in the same form (ie, tablet, capsule, suspension, etc.) as the brand-name product. The FDA requires bioequivalence (BE) studies.² These studies usually include fewer than 40 healthy individuals and must show that the generic product has the same pharmacokinetic profile as the brand-name drug (the active ingredient already has been shown to be safe and effective). The generic product can deviate from the brand product’s profile by a set amount—currently a 90% confidence interval limit of 80% to 125%.² This means that pharmacokinetic parameters such as max concentration (Cmax), time to max concentration (Tmax), mean absorption time, and area under the curve (AUC)—which is a measure of overall drug exposure—are no less than 80% and no more than 125% of the parameters seen with the brand-name product. This may seem like a large deviation, but the FDA reports that generally “small differences in blood levels—<4%—may exist in some cases between a brand and its generic equivalent.”¹

A new generic formulation does not have to be tested against other generic formulations, only against the brand-name drug. Therefore, 2 generic formulations may differ pharmacokinetically by more than a 4% difference if one product is on the low side of the BE limit and the other is on the high side. If a patient starts 1 generic and then switches to another, efficacy may be lost or side effects may emerge because of BE differences. In Mr. X’s case, it is possible that the new generic version of fluoxetine resulted in higher plasma drug levels that lead to recurrence of sexual dysfunction.

Exceptions

Generic medications are not recommended for certain medical conditions, such as epilepsy and some hormone replacement therapy, because of lack of satisfactory BE to the brand-name drug.³ For these conditions, generic medications may be used, but should not be substituted for the brand-name product without careful monitoring. Additionally, switching between different generic manufacturers should be avoided.

If you have a question about generic substitution, consult the FDA’s Approved drug products with therapeutic equivalence evaluations⁴—also known as the “Orange Book,” which is available online (see Related Resources). This resource provides guidance about which drugs are interchangeable. The Orange Book is the “gold standard” on approved drug products and their interchangeability.

The Table lists certain psychiatric medications that may have issues with generic substitutions. Most pharmacies stock and dispense only generic drugs that the FDA considers bioequivalent to the brand-name product.

Allergic reactions may occur because of different inert ingredients within each generic or brand-name drug. Generic drug manufacturers are not required to use the same inactive or “filler” ingredients. Some patients may be allergic to 1 version and may require a specific brand or generic version to overcome this potential allergy.³

Although most generic substitutions occur without incident, consider BE differences among products and your patient’s medical condition before initiating a switch. When switching between generics, carefully monitor your patient as you would when switching from the brand-name product to a generic. If new treatment-related issues arise or lack of efficacy occurs, ask your patient if the pharmacy switched to a new generic formulation.

Table

Bioequivalence among generic psychotropics: What to know before you switch

Related resources

• Food and Drug Administration. www.fda.gov/Drugs/default.htm.
• Generic Pharmaceutical Association. www.gphaonline.org.
• Food and Drug Administration. Orange book: approved drug products with therapeutic equivalence evaluations. www.accessdata.fda.gov/scripts/cder/ob/default.cfm.

Drug brand names

• Amitriptyline/Perphenazine • Triavil
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Venlafaxine • Effexor

Disclosure

Dr. Ellingrod is a member of an advisory board for Eli Lilly and Company.

Mr. X, age 47, suffers from major depressive disorder, which he developed 1 year ago after experiencing a myocardial infarction. At that time, Mr. X received brand-name fluoxetine (Prozac), 20 mg/d. After 4 weeks, his mood improved, but he experienced delayed ejaculation, which resolved spontaneously after 12 weeks of treatment.

Because Mr. X recently lost his job and health insurance, he inquires about lowering his health care costs. Discontinuing fluoxetine is not advised, so you recommend changing to a generic formulation. Mr. X tolerates this conversion without difficulty; however, 9 months later he reports he is experiencing delayed ejaculation again. He has had no changes in medical history and has not started any new medications. Mr. X claims he has been compliant with his medication, although he mentions that the fluoxetine tablets looked different when he refilled his prescription 2 weeks ago. You call the pharmacy and discover that they started dispensing generic fluoxetine from a different manufacturer around the time Mr. X refilled his prescription. You prescribe Mr. X his old version of generic fluoxetine, and his sexual dysfunction resolves within 2 weeks.

In the United States, 2.6 billion prescriptions—approximately 70% of all prescriptions—are filled using generic versions of brand-name products.¹ For most patients, generic substitution is acceptable and reduces costs. Although the practice has become routine, certain circumstances may make switching to a generic medication or between generic medication problematic. To understand why, it is important to discuss the FDA’s generic drug approval process.²

Bioequivalence

Pharmaceutical manufacturers developing a generic drug must create a product that will deliver the same amount of medication at the same rate and in the same form (ie, tablet, capsule, suspension, etc.) as the brand-name product. The FDA requires bioequivalence (BE) studies.² These studies usually include fewer than 40 healthy individuals and must show that the generic product has the same pharmacokinetic profile as the brand-name drug (the active ingredient already has been shown to be safe and effective). The generic product can deviate from the brand product’s profile by a set amount—currently a 90% confidence interval limit of 80% to 125%.² This means that pharmacokinetic parameters such as max concentration (Cmax), time to max concentration (Tmax), mean absorption time, and area under the curve (AUC)—which is a measure of overall drug exposure—are no less than 80% and no more than 125% of the parameters seen with the brand-name product. This may seem like a large deviation, but the FDA reports that generally “small differences in blood levels—<4%—may exist in some cases between a brand and its generic equivalent.”¹

A new generic formulation does not have to be tested against other generic formulations, only against the brand-name drug. Therefore, 2 generic formulations may differ pharmacokinetically by more than a 4% difference if one product is on the low side of the BE limit and the other is on the high side. If a patient starts 1 generic and then switches to another, efficacy may be lost or side effects may emerge because of BE differences. In Mr. X’s case, it is possible that the new generic version of fluoxetine resulted in higher plasma drug levels that lead to recurrence of sexual dysfunction.

Exceptions

Generic medications are not recommended for certain medical conditions, such as epilepsy and some hormone replacement therapy, because of lack of satisfactory BE to the brand-name drug.³ For these conditions, generic medications may be used, but should not be substituted for the brand-name product without careful monitoring. Additionally, switching between different generic manufacturers should be avoided.

If you have a question about generic substitution, consult the FDA’s Approved drug products with therapeutic equivalence evaluations⁴—also known as the “Orange Book,” which is available online (see Related Resources). This resource provides guidance about which drugs are interchangeable. The Orange Book is the “gold standard” on approved drug products and their interchangeability.

The Table lists certain psychiatric medications that may have issues with generic substitutions. Most pharmacies stock and dispense only generic drugs that the FDA considers bioequivalent to the brand-name product.

Allergic reactions may occur because of different inert ingredients within each generic or brand-name drug. Generic drug manufacturers are not required to use the same inactive or “filler” ingredients. Some patients may be allergic to 1 version and may require a specific brand or generic version to overcome this potential allergy.³

Although most generic substitutions occur without incident, consider BE differences among products and your patient’s medical condition before initiating a switch. When switching between generics, carefully monitor your patient as you would when switching from the brand-name product to a generic. If new treatment-related issues arise or lack of efficacy occurs, ask your patient if the pharmacy switched to a new generic formulation.

Table

Bioequivalence among generic psychotropics: What to know before you switch

Related resources

• Food and Drug Administration. www.fda.gov/Drugs/default.htm.
• Generic Pharmaceutical Association. www.gphaonline.org.
• Food and Drug Administration. Orange book: approved drug products with therapeutic equivalence evaluations. www.accessdata.fda.gov/scripts/cder/ob/default.cfm.

Drug brand names

• Amitriptyline/Perphenazine • Triavil
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Venlafaxine • Effexor

Disclosure

Dr. Ellingrod is a member of an advisory board for Eli Lilly and Company.