Dose-dumping

The advantages of this type of system are that the release rates are independent of the dmg properties, macromolecules and ionic species may be dehvered, fluxes may be high, and release rates are not dependent upon environmental conditions such as pH. The disadvantages are that the system is subject to dose-dumping if it is chewed. It is also more expensive to formulate than coating tablets, and there is a possibiUty of hole plugging. 

L Hendeles, M Weinberger, G Milavetz, M Hill III, L Vaughan. Food-induced dose-dumping from a once-a-day theophylline product as a cause of theophylline toxicity. Chest 87 758-765, 1985. 

The dissolution specification for prolonged-release dosage forms should cover a minimum of three points one to ensure that dose-dumping does not occur (early, typically 20-30% release), one to confirm compliance with the dissolution curve profile (around 50% release), and one to ensure that the majority of the dose has been released (often more than 80% released). The robustness of the test procedure should be considered (e.g., to temperature, pH, and rotational speed). 

Fluphenazine should be initiated at 5 mg/day to treat schizophrenia and increased as needed. The depot form is administered every 2 weeks in doses from 6.25 to 50mg per dose. The depot form is generally believed to cause less EPS however, some physicians have raised the concern that depot fluphenazine may be prone to dose dumping. Dose dumping means that a significant portion of the depot dose might be prematurely released into the bloodstream. 

Like fluphenazine, haloperidol is available in oral, injectable, and depot forms. In schizophrenia, haloperidol is begun at doses of 5 mg daily and increased as needed. Lower doses are used for most other indications. The depot form of haloperidol is initiated by administration of a 50mg test dose. Depot haloperidol is given monthly at about 20 times the daily dose of the oral form. The maximum depot dose is 200 mg per month. Dose dumping does not seem to be a problem with depot haloperidol. 

Fluphenazine decanoate may cause more acute EPS than haloperidol decanoate due to a phenomenon known as dose dumping. Here, a small amount of depot formulation is released into the systemic circulation shortly after an injection. There may be a tendency for haloperidol to be more effective for a subset of schizophrenic symptoms, less depressogenic, and slightly less likely to exacerbate extrapyramidal symptoms. These effects, however, are not large, may not be clinically significant, and are not consistently evident in all studies. 

Time-release technology from the time of the OTC review (1970s) was prone to dose-dumping. 

Depending on the country where the drug is manufactured, a number of different time-release preparations are available. Palladone , a controlled-release preparation consisting of hydromorphone HC1 pellets, was withdrawn from the U.S. market in 2005. When taken with alcohol the pellets rapidly released their contents leading to dangerously elevated peak plasma concentrations.60 Interaction with ethanol and dose dumping is not the only concern. Any CNS depressant may enhance the depressant effects of hydromorphone. 

The BA profile established for the drug product rules out the occurrence of any dose dumping. 

An f2 value between 50 and 100 suggests that the two dissolution profiles are similar, indicating the test formulation is bioequivalent to the reference formulation.1 There are a minimum of three timepoints in extended release dosage forms an early timepoint that detects dose dumping, a middle point, and a not-less-than (NLT) 80% point. More points may be added, especially for very long drug release testing periods. 

Disadvantages of Controlled Drug Release. Potential disadvantages of controlled release dosage forms include the possibility of dose dumping, less facile dose adjustment, increased potential for hepatic first-pass metabolism, possible delay in onset of action, possibly lower system availability, and time of drug release limited to residence time of formulation in the optimum absorption region(s) of GI tract. 

Fig. 6 Theophylline serum concentration in an individual subject after a single 1500 mg dose of Theo-24 taken during fasting, period during which this patient experienced nausea, repeated vomiting, or severe throbbing headache. The pattern of drug release during the food regimen is consistent with dose-dumping. (From Ref. l)...

Reduced dose dumping potential compared to large implantable devices... 

D Arcy PF. Theophylline toxicity from dose-dumping. Pharm Int 1985 6 289. 

Absence of any chance of dose dumping , because the gross weight of active drug in a single slow-release capsule will always exceed that of a single dose of the prototype. 

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