USE of GENERIC MEDICINES and the OFF-LABEL USE of MEDICINES in PSYCHIATRY GUIDELINE DOCUMENT

USE OF GENERIC MEDICINES and the OFF-LABEL USE OF MEDICINES IN PSYCHIATRY – GUIDELINE DOCUMENT (For discussion)

INTRODUCTION

Over the last few years, the pharmaceutical landscape that affects psychiatrists in South Africa (as in the rest of Africa and the world) has been changing rapidly with the introduction of a wide range of generic alternatives for medicines used to treat mental disorders. This has been accompanied by the emergence of many new “generic” pharmaceutical companies now being involved in psychiatry. Several of these “generic companies” now also produce original products. Existing multinational companies also have introduced their own ranges of generic alternatives, or so called “clone” preparations (cheaper versions of existing products). At present, the line between pure “generic” and “ethical” companies is becoming increasingly blurred.

For psychiatrists, this has meant getting used to different versions of known drug formulations, new companies and their representatives, and varied reactions to existing drugs by their patients. Legislation passed in South Africa has required pharmacists, when dispensing medication, to offer patients a generic alternative provided that it is cheaper than the originator product and substitution has not been prohibited by the prescribing practitioner (Medicines and Related Substances Control Amendment Act which came into legislation on 02 May 2003). Patients in turn have had to get used to their medications changing in appearance, packaging and branding – as can be expected, the reaction has been mixed.

Most Medical Aids/Funders in South Africa underscore the use of generic medicines – for some psychiatrists in private practice, this has resulted in frustration and a perception that they are being prescribed to as far as patient management is concerned. There is a perception that the “power” as far as prescription is involved has been removed from the psychiatrist, but that they are still expected to take responsibility for what happens to the patient taking the medication. For some, there is the perception that generic drugs are “inferior” as they have had to deal with apparent relapses in patients when switched to these alternatives. In the state hospitals, generic medicines are also widely used, and emerging problems are similar to those experienced by private psychiatrists. A problem that has shown itself in both sectors is the fluctuating availability of drugs, and patients having to get used to taking different looking/packaged drugs every time they see the pharmacist. Often patients that prefer taking originator drugs are required to make a co-payment.

Worldwide, there is an increase in the use of generic medicines, primarily in an attempt to drive down the costs of healthcare. The World Health Organization is supportive of the development and use of generic medicines. Incountries such as the USA, the use of generic medicines has now exceeded that of originator products. With South Africa confronting the realities of its own healthcare situation, and attempting to make health care more affordable, it has become inevitable that generic medicines are part of the treatment package. With the implementation of the National Health Insurance legislation, generic medicine will probably constitute a significant component of providing broader access to health care.

Concern has been expressed by psychiatrists that generic medicines may have demonstrated bioequivalence to originator products, but that their “therapeutic equivalence” should be subject to scrutiny. There is also the perception in some quarters that generic medicines are “fast tracked” in the process of registration with the Medicines Control Council.

Against the backdrop of the above, a Generic Task Team was commissioned by SASOP in 2008 to address the problems that psychiatrists, and their patients have encountered, and to pave the way for a healthy relationship with ALL role players in the pharmaceutical industry. This document is the culmination of a process of discussion and consultation between SASOP and the pharmaceutical industry, specifically the NAPM (representing most of the generic companies) and PIASA (representing most of the multinational/originator companies).

Bioequivalence as the golden standard: from our discussions with the pharmaceutical companies, the following emerged:

Bioequivalence testing is an internationally accepted surrogate for therapeutic equivalence of generics.
+-60% of FDA registrations for originators are based on bioequivalence.
Many originator companies are going to be operating in the generic market and hence the bioequivalence issue is going to become less important. e.g. GSK/ Aspen, Sanofi-Aventis & Winthrop, Pfizer/Aurobindo.
Bioequivalence testing is a pharmaceutical industry tool that is applied to both originator and generic products during the registration period.

It became clear that bioequivalence was the only standard that would be applied and that it is the accepted norm by most regulatory authorities. It would therefore be futile to pursue the matter of bioequivalence vs therapeutic equivalence any further. It was agreed however, that certain factors besides bioequivalence could affect the outcome that patients have in response to taking different preparations: Psychosomatic symptoms/ the “Label Effect” / the natural course of the disease / insufficient treatment can all account for the reports of product/medicine failure.

Quality control: while bioequivalence is most certainly an instrument used during the registration of drugs, quality control needs to be implemented during the manufacturing process and this function resides with the MCC as well. Medicines need to be produced according to “Good Manufacturing Process” and this needs to be monitored – for example, can the bioequivalence that was demonstrated at the time of registration still be demonstrated a few years later when the medicine is on the open market? Is the quality of the medicine being maintained?
Patients who relapse when being switched:

-Should a patient be switched from one drug to a generic alternative, or from one generic to another, and relapse, or not respond appropriately, the prescribing psychiatrist should report this to the manufacturing company i.e. start by filling out the product complaint forms and getting following up from the relevant company. SASOP and healthcare professionals also need to be more vigilant about reporting adverse events.

-The appropriate form needs to be completed when reporting to the MCC – (see attached). Psychiatrists are encouraged to report any problems encountered with medicine substitution, a perceived lack of effect of medicines, or quality issues to the MCC and to the Generic Medicines Task Team of SASOP as soon as possible.

Pts started on medication should remain on the same product:build into the guidelines. It is desirable that patients who are suffering from psychiatric disorders, and who have been stabilized on medication, should continue as far as possible, to receive the same medication/product on repeat prescriptions to rule out problems with therapeutic efficacy arising from substitution. Should a generic drug be prescribed, it is desirable that the drug not be substituted with an alternative generic drug for the same reason. Bearing in mind that pharmacists are compelled by law to offer patients a generic alternative (when available), psychiatrists should try and stabilize patients on medications that are affordable to the patient from the start (bearing in mind what the status of the patient is as far as medical insurance or lack thereof is).

IN SUMMARY:

SASOP acknowledges that the use of generic medicines is an important step in making mental healthcare accessible to all in South Africa.
It is important that all medicines on the market in South Africa should be subjected to the same, rigorous assessment (which would include bioequivalence as the golden standard), before being marketed and used in patients with psychiatric disorders.
Once a medicine is on the open market, regular inspections by the Medicines Control Council (MCC) should ensure ongoing quality and consistency of the product.
Psychiatrists who believe that there is some inconsistency in the quality of the product should:

Avail themselves of the batch number of the medicine used,
Report the problem to the manufacturing company and the MCC by filling out the specified forms,
Report the matter to the Generic Task Team of SASOP.

Psychiatrists should, when making decisions about the specific treatment of a patient, also consider the affordability of the prescribed medicines to the patient and should commence treatment with medicines that are affordable from the start.
It is desirable that patients being treated for psychiatric disorders, once started and stabilised on a product, should remain on the productfor at least one yearand not be switched from one generic alternative to the other.

The “off-label” use of medicines in psychiatry

The term ‘off-label’ means that the medicine is used in another way or for an indication other than those specified in the conditions of registration of the medicine and as reflected in its labelling. It does, however, not necessarily imply that the medication is not effective or is unsafe to be used in this way. Off-label use has become an important part of mainstream, legitimate medical practice worldwide and is especially common in oncology, obstetrics, paediatrics, infectious diseases (notably HIV) and rare diseases. Rita-Marié Jansen Department of Private Law University of the Free State Bloemfontein SAMJJune 2009, Vol. 99, No. 6

Off-label use of psychotropic medication is widespread.

Unlicensed use of licensed drugs is a common feature of prescribingin general psychiatry settings. It is also commonplace in child and adolescent psychiatry and psychiatry of old-age where drugs may be used outside of their specified age-range. Sometimes drugs are used outside of the registered dose-range.

This is partly due to the problem with diagnosis in psychiatry. We are often uncertain about diagnosis, tend to treat symptoms, have high placebo response rates, and do not always have adequate evidence based results to back up what we do.

Kavi et al, 2009: 88.5% of all DSM-IV-TR categorized disorders lack an approved medication for their treatment. Atypical Antipsychotics had the most extensive off-label use for a DSM-IV-TR categorized disorder, whereas Mood Stabilizers showed the greatest off-label use with regards to disorders and symptoms that are not DSM-IV classified. For each class of medications, more off-label uses exist than FDA-approved uses.

Examples of off-label or “unlicensed” prescription: (Baldwin and Koski, 2007)

The disorder: The first type is perhaps the best known and involves the prescriptionof a medication for an indication that is not covered withinthe terms of the marketing authorisation.
However, new indicationsfor existing treatments appear regularly, as shown by the expansionof indications for some of the selective serotonin reuptakeinhibitors (SSRIs), so what is unlicensed prescribing one monthmay come within the terms of the marketing authorisation thenext. Conversely, drugs may ‘lose’ an indicationas new clinical data emerge and become available to regulatorybodies; an example of this is changes to the licensing of SSRIs(other than fluoxetine) for the treatment of depression or obsessive–compulsivedisorder in children and adolescents. A different example isthe removal in the UK of premenstrual dysphoric disorder fromthe licensed indications for fluoxetine, as a result of theharmonisation of the summary of product characteristics forfluoxetine with Europe (the indication persists in the USA).
The demographics: The second type of unlicensed prescribing involves a drug beinggiven to a patient who is outside the age range specified withinthe summary of product characteristics.
The March 2007 BNF in the UK statesthat prescribing the noradrenaline reuptake inhibitor reboxetineto children and elderly patients is ‘not recommended’(British Medical Association & Royal Pharmaceutical Society of Great Britain, 2007)(even though a randomised controlled trial has documented itsefficacy in the treatment of depression in elderly patients).For instance, prescription of reboxetine to a 65-year-old patientis licensed, but it becomes unlicensed when they turn 66, eventhough it is unlikely that they will differ much in their metabolismand response to antidepressant treatment when they cross thethreshold of their 66th birthday. When selecting patients forinclusion in a drug trial it is common practice to set an arbitraryupper age limit (usually around 70 years). Exclusion of adolescentsor children is also routine, although in this case considerationsof capacity to give consent, as well as differences in pharmacokinetics,make this more defendable. All of the available SSRIs have provenefficacy in the treatment of obsessive–compulsive disorder,and some have efficacy in randomised controlled trials conductedin children and adolescents. The March 2007 BNF notes that twoSSRIs (fluvoxamine, aged 8 years and over; sertraline, 6 yearsand over) can be used in the treatment of children with thedisorder (British Medical Association & Royal Pharmaceutical Society of Great Britain, 2007).
The dose: Another type of unlicensed prescribing is the use of a medicineoutside the dose range recommended in the summary of productcharacteristics and reflected in the BNF.
High-dose antidepressants(e.g. venlafaxine at more than 375 mg a day) are sometimes recommendedby tertiary services in the management of treatment-resistantdepression; similarly, supra-BNF dosing with antipsychoticsis not uncommon in forensic practice, especially in the managementof treatment-resistant psychosis. However, the effectivenessof these strategies is uncertain.
The duration: There is another type of unlicensed prescribing, representingthe use of a licensed medication for longer periods than thosespecified within the marketing authorisation.
For example, mostanti-depressants are licensed for treating ‘depressiveillness’. Continuation and maintenance treatment withantidepressants of people with recurrent depressive disorderwhen they are asymptomatic and in remission might technicallytherefore represent unlicensed use, but also clearly representsan aspect of good clinical practice. The Committee on Safetyof Medicines currently advises that prescription of benzodiazepinesshould be limited to 4 weeks only (reflected in Section 4.1of the BNF ; British Medical Association & Royal Pharmaceutical Society of Great Britain, 2007),but many people with chronic and disabling anxiety disorderswho have not responded to other treatments may benefit fromlonger courses of treatment (Haw & Stubbs, 2006).

Must the patient be informed that the medication is used off-label?

The doctrine of informed consent requires the medical practitioner to give a patient the material information regarding the proposed treatment, alternatives, potential risks and benefits of each potential treatment, and the result of no treatment. Most judgments in the USA21 view that use of medication off-label pertains to the regulatory status of the medication only and is not relevant medical information that must be disclosed to the patient, but this remains a contentious topic.

The opposing argument is that off-label use lacks the assurances of safety and efficacy that an approved indication has, which is important information the reasonable patient would want to know before making a decision.15 Because there is no case law on this in South Africa the court may hold that a finding of lack of informed consent cannot be based solely on the off-label status of the medication not being revealed.

Generally speaking it would be good medical practice to reveal the off-label use of medication. If not revealed it could, for instance, confuse the patient should he or she read the package insert. This information can also be important to determine whether the medical aid fund will pay for the treatment. To safeguard against possible litigation it is highly recommended that practitioners should discuss the off-label use of medication with their patients and document the discussion. Informed consent is imperative if there is little research or other evidence of current practice, or if the use of the medicine in this way is innovative.

Procedure to follow when prescribing medicines off-label:

If medication is to be used off-label, the treating physician should first make sure that registered medications have been considered and used.
The treating physician should then avail him/herself with the evidence available regarding the use of the medication off-label.
The treating physician should balance the benefits and risks of prescribing the medication, discuss this with the patient and document this process.
A cautious trial of an off-label drug should be initiated and the patient should be monitored carefully for any adverse reactions. Therapeutic efficacy, or lack thereof, should be documented.
If there are concerns either from the patient or the treating physician, a second opinion on the off-label use should be sought from a more experienced physician. This opinion should be documented.
Caution should be exercised when using medications in vulnerable patient populations such as children and adolescents, the elderly, and those with impaired insight and judgement.

IN SUMMARY:

SASOP acknowledges that the off-label use of medicines to treat psychiatric disorders is commonplace and acceptable practice. To this end, medical insurance companies should reimburse patients for the expenses involved in using this medication.
However, off-label use of medication should be done cautiously and the process should be well-documented, bearing in mind the level of evidence that exists for such off-label use.
Patients should be informed when the use of medicines is off-label and informed consent obtained.