Vet360 Vol 4 Issue 3 June 2017 Vet360 - Page 19

PHARMACOLOGY be highly sound , and has been used to bring numerous generic medications onto the market over the last 40 years , with no proof existing that a generic is inferior when used for its registered indication . The science is so sound , that the innovator company also relies on the same methodology when they want to change their formulation e . g . when a tablet is changed to a palatable tablet , bioequivalence testing is used to save on costs and prevent retesting as once again , there is no need to repeat all the tests . All in all , if a generic formulation is registered and the company follows GMP , there should be no difference between a generic and an innovator .
Nonetheless an important concept in generic medication development is the concept of switchability and prescribability .
• Generics are interchangeable and any of the registered formulation for a particular species can be considered a valid effective choice at the start or initiation of treatment in a patient . This is known as prescribability i . e . the choice is open when the drug is first prescribed .
• However this scenario changes when one is treating a chronic condition where the patient has been stabilised on treatment with a particular formulation e . g . epilepsy . Under these conditions , it is not advisable to switch formulations acutely ( irrespective of whether it a generic or innovator ) acutely . This acute switching can only occur if the products are tested for switchability , which most formations are not e . g . one can chose to use formulation A or formulation B initially ( at this stage there is no difference ). However at the end of the month , stick to the same formulation and don ’ t change acutely as this can be dangerous and result in destabilisation ( i . e . for chronic patients , stock the same formulation ). If you do need to change formulation , it ’ s always safer to phase out the old formulation while the new formulation is phased in .
• Compounded formulations : These are formulations that are meant for use in an individual patient and are tailor made drugs , usually made by a pharmacist on an “ as needed ” basis . Compounded formulations are generally simple formulations with the active dispersed in an excipient . These compounded products , due to their individualised nature , don ’ t need to legally comply with GMP requirements , and thus may be open to all the problems mentioned above . For this reason , the use of compounded products from a safety point to the patient and consumer , should not be used when there are alternate registered products i . e . legally one takes responsibility for the use . More importantly , it may be more difficult legally to demonstrate that the use of the compounded product use was prudent when there are GMP approved alternates available . Also of importance to consider is the product ’ s sterility and purity and shelf life . Since this may be a problem , compounded products should ideally be limited to oral or topical use ; and they should not be used in production animals .
Is a Generic , definitely a generic ?
This may seem as an odd question , in light of what has been said above . But it ' s important to know the constraints of the process of bioequivalence . The foremost principle of bioequivalence is the comparison of the plasma profile between the test and reference product , and show that they ’ re essentially identical . However as mentioned under pharmacokinetics , the PK of a drug is dependent on a number of factors such as absorption and elimination . This would mean that the profile is dependent on the species of testing and the metabolism of the drug . As such , when bioequivalence is shown , each profile has to be determined for each the different route recommended and in each of the different species it is indicated for . As an example , a drug recommended for use by the subcutaneous and intramuscular in pigs , cattle and horses , will need to be tested in six separate studies to show that all the routes per species are bioequivalent . Since it may not always be possible demonstrate bioequivalence in all these studies , some generic formulations will have curtailed claims . As such it is important to check what the recommendation are on the package instead of assuming that they are the same as the innovator ( reference product ).
Another important consideration is the use of human medication in animals . Firstly this extra-label use of the drugs has legal implications , as the person recommending this use , takes responsibility if something goes wrong ( for registered veterinary drugs used correctly as stated on the package insert , the registration owner takes responsibility ). The use of human drug extra-label is nonetheless considered safer than using a compounded product , as good manufacturing practice is still in place as it ’ s a registered human product ( i . e . same liability , but lower risk ) ( Table 2 ).
As a veterinarian , it is incumbent on you to make use of your professional judgement when choosing to use a human formulation . Firstly consideration must be given to the dose , which means that one needs to take into consideration the studies that have demonstrated that this extra-label use is prudent . For the latter consideration needs to be given to the sample size , as registered product use a substantial number of clinical cases to prove that the effect is real ( as large as a few hundred animals ) i . e . the published study on extra-label use may only have included a small number of clinical cases and not taken into consideration intra-subject variability in effect and side effects . Another important consideration would be that the product used in the publication , may not necessarily be the same product that is sold locally e . g . There are numerous cases of companies choosing to market different formulations in different countries for various manufacturing reasons even though the name is the same . It is possible that the published formulation may have a different response to the South African available drug , purely because they are of different formulation .
Issue 03 | JUNE 2017 | 19
PHARMACOLOGY be highly sound, and has been used to bring numer- ous generic medications onto the market over the last 40 years, with no proof existing that a generic is inferi- or when used for its registered indication. The science is so sound, that the innovator company also relies on the same methodology when they want to change their formulation e.g. when a tablet is changed to a palatable tablet, bioequivalence testing is used to save on costs and prevent retesting as once again, there is no need to repeat all the tests. All in all, if a generic for- mulation is registered and the company follows GMP, there should be no difference between a generic and an innovator. Nonetheless an important concept in generic med- ication development is the concept of switchability and prescribability. • Generics are interchangeable and any of the reg- istered formulation for a particular species can be considered a valid effective choice at the start or initiation of treatment in a patient. This is known as prescribability i.e. the choice is open when the drug is first prescribed. • However this scenario changes when one is treat- ing a chronic condition where the patient has been stabilised on treatment with a particular formulation e.g. epilepsy. Under these conditions, it is not ad- visable to switch formulations acutely (irrespective of whether it a generic or innovator) acutely. This acute switching can only occur if the products are tested for switchability, which most formations are not e.g. one can chose to use formulation A or for- mulation B initially (at this stage there is no differ- ence). However at the end of the month, stick to the same formulation and don’t change acutely as this can be dangerous and result in destabilisation (i.e. for chronic patients, stock the same formulation). If you do need to change formulation, it’s always safer to phase out the old formulation while the new for- mulation is phased in. • Compounded formulations: These are formulations that are meant for use in an individual patient and are tailor made drugs, usually made by a pharma- cist on an “as needed” basis. Compounded formu- lations are generally simple formulations with the active dispersed in an excipient. These compound- ed products, due to their individualised nature, don’t need to legally comply with GMP requirements, and thus may be open to all the problems mentioned above. For this reason, the use of compounded products from a safety point to the patient and con- sumer, should not be used when there are alternate registered products i.e. legally one takes responsi- bility for the use. More importantly, it may be more difficult legally to demonstrate that the use of the compounded product use was prudent when there are GMP approved alternates available. Also of im- portance to consider is the product’s sterility and purity and shelf life. Since this may be a problem, compounded products should ideally be limited to oral or topical use; and they should not be used in production animals. Is a Generic, definitely a generic? This may seem as an odd question, in light of what has been said above. But it's important to know the con- straints of the process of bioequivalence. The fore- most principle of bioequivalence is the comparison of the plasma profile between the test and reference product, and show that they’re essentially identical. However as mentioned under pharmacokinetics, the PK of a drug is dependent on a number of factors such as absorption and elimination. This would mean that the profile is dependent on the species of testing and the metabolism of the drug. As such, when bioequiva- lence is shown, each profile has to be determined for each the different route recommended and in each of the different species it is indicated for. As an example, a drug recommended for use by the subcutaneous and intramuscular in pigs, cattle and horses, will need to be tested in six separate studies to show that all the routes per species are bioequivalent. Since it may not always be possible demonstrate bioequivalence in all these studies, some generic formulations will have curtailed claims. As such it is important to check what the recommendation are on the package instead of assuming that they are the same as the innovator (ref- erence product). Another important consideration is the use of human medication in animals. Firstly this extra-label use of the drugs has legal implications, as the person rec- ommending this use, takes responsibility if something goes wrong (for registered veterinary drugs used cor- rectly as stated on the package insert, the registration owner takes responsibility). The use of human drug extra-label is nonetheless considered safer than us- ing a compounded product, as good manufacturing practice is still in place as it’s a registered human prod- uct (i.e. same liability, but lower risk) (Table 2). As a veterinarian, it is incumbent on you to make use of your professional judgement when choosing to use a human formulation. Firstly consideration must be given to the dose, which means that one needs to take into consideration the studies that have demon- strated that this extra-label use is prudent. For the latter consideration needs to be given to the sample size, as registered product use a substantial number of clinical cases to prove that the effect is real (as large as a few hundred animals) i.e. the published study on ex- tra-label use may only have included a small number of clinical cases and not taken into consideration in- tra-subject variability in effect and side effects. An FЦW"'FB66FW&FvVB&RFBFR&GV7@W6VBFRV&Ɩ6FBV6W76&ǒ&RFP6R&GV7BFB26B6ǒRrFW&R&RVW"ЦW266W2b6W266rF&WBFffW&V@f&VF2FffW&VB6VG&W2f"f&W2RЦf7GW&r&V62WfVFVvFRR2FR6RगB276&RFBFRV&Ɨ6VBf&VFfPFffW&VB&W76RFFR6WFg&6f&PG'VrW&Vǒ&V6W6RFW&RbFffW&VBf&VFग77VR2TR#r