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• W1747804906 abstract "To the Editors: Variation in impurity levels is always significantly different from manufacturer to manufacturer of the same kind of drug (Wirth et al., 2000; Sabroe, 2006). Drug-related impurities (even toxicologically qualified impurities) may have inappropriate pharmacokinetic properties and significant pharmacological effects (FDA, 2004; EMEA, 2006). Medication switch may therefore have serious clinical consequences for patients taking some anticonvulsant drugs. The Active Pharmaceutical Ingredients (APIs) and the final drug products of different (generic) versions of a drug have to be the same—that is, within an agreed percentage (typically 98–100% for APIs and 95–100% for final drug products). The remaining percentage (0–5%) consists of one or more impurities—for example, stereoisomers (FDA, 1992) which may have totally different and inappropriate pharmacokinetic properties (absorption, distribution, biotransformation, and excretion) and quantitatively or qualitatively different pharmacological or toxicological effects compared to the APIs. For those anticonvulsant drugs which can be defined as critical dose drugs (e.g., lamotrigine at high dose or phenytoin at all doses) (Alloway et al., 2000; Morgan et al., 2005), small variations in the impurity profiles between generics from different manufacturers can cause toxic effects and/or seizures when taken by patients with epilepsy. Even an abrupt medication switch to a purer product can have serious clinical consequences as described in the following example. A patient with a daily dose at 800 mg switches from branded (assay = 99%+ 1% toxicologically qualified impurity) to a generic version (assay = 100%). The plasma concentration remains unchanged, but the impurity in the branded drug is 10 times more pharmacologically potent (which is not uncommon for stereoisomers) (FDA, 1992). This switch therefore results in a remarkable decrease in efficacy cause by a reduced daily dose from the branded 880 mg (800 mg + 8 mg × 10) to the generic 800 mg. Consider another example: A patient with a daily dose at 800 mg switches to another drug that complies with specification and contains 0.5% more of a toxicologically qualified impurity. The plasma concentration remains unchanged. However, the impurity is, for example, 10–100 times more pharmacologically potent compared to the API (which is not uncommon for stereoisomers) (FDA, 1992). This medication switch results in an abrupt daily intake of extra 800 mg × 0.5%= 4 mg which is 10–100 more potent corresponding to “40–400 mg” and which either has additive effect (the patient gets an overdose) or has an inhibit effect on the 800 mg (the patient will notice a remarkably decreased effect) depending on the mechanism of the biological activity of the impurity. The Danish licensing authority only permits a ±10% difference in bioavailability between a generic and an original anticonvulsant (The Danish Medicines Agency, 2007), yet medication switch still has serious consequences for patients with epilepsy taking high doses of lamotrigine. As a consequence, the Danish licensing authority now reimburse the cost difference between generic and proprietary for all patients with epilepsy taking high doses of lamotrigine >30 μmol/L to eliminate the risks which are associated with arbitrary switching among the drugs (The Danish Medicines Agency, 2007). The consistency of supply of the same drug seems to be important for patients taking antiepileptic drugs (AEDs). The switchback rates from generic to branded AEDs due to adverse effects are substantially higher (20%) than for non-AEDs (1.5–2.9%) (Andermann et al., 2007). Any recommendation in this area should tighten the focus on the consequences of significantly different impurity profiles between different manufacturers, as drug-related impurities can have inappropriate pharmacokinetic properties and pharmacologic effects (FDA, 1992). This understanding, combined with the fact that there are no thresholds in international drug regulation (FDA, 2004; EMEA, 2006) with respect to the pharmacological effects and pharmacokinetic properties of drug related impurities, should make it clear that medication switch may have serious clinical consequences for patients taking some anticonvulsant drugs in spite of plasma concentration remains unchanged as described in example 1 and 2. Therefore, it should be the responsibility of everyone in the patient management pathway to be aware of the consistency of supply issue so that patients taking anticonvulsant drugs defined as critical dose drugs always receive the same drug, whether branded or not." @default.
• W1747804906 created "2016-06-24" @default.
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• W1747804906 date "2008-01-01" @default.
• W1747804906 modified "2023-09-27" @default.
• W1747804906 title "Impurities-The hidden danger in anticonvulsant drugs" @default.
• W1747804906 cites W2015221510 @default.
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• W1747804906 doi "https://doi.org/10.1111/j.1528-1167.2007.01329_3.x" @default.
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