Evidence-Based Reviews

Worried about high-dose prescribing? Manage risk for you and your patient

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Communicate and document informed consent when using medications off-label.


 

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Mr. B, age 35, is admitted for the fourth time to the inpatient service with hallucinations and delusions related to chronic schizophrenia. After appropriate attempts to control his symptoms, he has begun to respond to usual treatment with an atypical antipsychotic. He remains a “partial responder,” however, at the maximum FDA-approved dosage listed in the package insert (PI). What do you do next?

Because of this author’s (NSK) dual training in medicine and forensic psychiatry, other clinicians often ask me about patients such as Mr. B. Prescribing for patients who do not respond to standard dosages can create anxiety about going “off-label.” This article describes how to manage potential risk to yourself and your patient by communicating effectively and documenting informed consent.

What are the options?

To effectively treat Mr. B’s symptoms, you could:

  • change medications and start over
  • augment with a second atypical antipsychotic
  • stay with the antipsychotic to which he has shown partial response, but go above the PI dosing.
Each strategy could pose problems, but most psychopharmacologists would choose the third option—the most logical one.

Changing medications is attractive, but the choice of an atypical antipsychotic with relative metabolic neutrality is limited, and “switching” is time-consuming. When a drug begins to show efficacy, most clinicians won’t opt to “change horses midstream”—especially if managed care is pressuring for rapid discharge.

Augmentation introduces polypharmacy and potential drug-drug interactions. Very little evidence guides us in combining antipsychotics, as most manufacturers will never study the coadministration of 2 branded medications with the same indication.

Only a few case reports have described combining atypical antipsychotics.1-4 Moreover, many managed care providers and governmental payers/regulators will not pay for polypharmacy with 2 atypical antipsychotics or will allow it only during cross-tapering from one agent to another.

‘High-dose’ monotherapy is the choice most often taken by clinicians and experts. Pharmaceutical manufacturers study a wide range of doses during medication development. Two pivotal trials form the basis of the New Drug Application for FDA approval and largely dictate the PI language.

Don’t misconstrue the PI dosing as optimal for a specific medication or patient. Historically, FDA-approved dosing for atypical antipsychotics has been too high (risperidone, aripiprazole) or too low (ziprasidone, quetiapine) for many patients we treat, even when the medications are used as indicated. This problem is magnified when clinicians try to make individual patients (N=1) resemble the average pooled analysis of the clinical trial group (N>200) and find that the individual patient may be a low-dose, average-dose, or high-dose responder (Table 1).

Informed prescribing. Polypharmacy is a complex issue because essentially no pharmacokinetic or pharmacodynamic studies have examined the simultaneous use of ≥3 psychotropics. When a pharmacist or drug interaction computer alerts you to a potential drug-drug interaction, the warning is almost always theoretical. No real data exist about coadministering most medications.

Physicians may query a manufacturer about off-label, above-PI dosing data by contacting the company’s medical information department or asking a pharmaceutical representative. What you receive will vary by manufacturer, but in almost every case you will get the safety data you want. Occasionally you also will get efficacy data, which is nice but not crucial. An online literature search of MEDLINE is another way to obtain this information.

Table 1

Patient factors that influence response to medication

Patient body mass, age, race, ethnicity, and gender
Variability in medication absorption
Hepatic metabolizing factors
How ‘sick’ the patient is, compared with those in pivotal clinical trials
Patient’s behavior, lifestyle, habits, and diet
Comorbid medical conditions
Other psychiatric and nonpsychiatric pharmacotherapy

Liability risk?

Every clinician I’ve met prescribes drugs off-label, whether in terms of dose, indication, or age limits in the PI as published in the Physicians’ Desk Reference (PDR).5 Still, nearly all describe to me the following nightmare, in which they “violated” the PI and “something bad” happens.

They are sitting in court on the witness stand, white-knuckled and sweaty, as a plaintiff’s attorney strolls up to them, PDR in hand, and says: “Doctor, isn’t this the Bible, and you violated the Bible?” And thus is born the fear of a malpractice claim, predicated on off-label dosing.

Off-label prescribing is rarely the only issue in a lawsuit, according to Denny Rodriguez, assistant vice president, claims, Professional Risk Management Services (PRMS), Inc.—manager of The Psychiatrists’ Program endorsed by the American Psychiatric Association. When raised, allegations related to off-label prescribing are among many presented by the plaintiff under the rubric of treatment that violated the standard of care.

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