Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)- FDA

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Nifedipine once-daily products may not differ markedly in single-dose studies with fasted administration. However, after fed administration, none of the generics tested were bioequivalent to nifedipine GITS. Changes in the SNS are apparent when a pressor agent is administered, with increases in BP and reduced heart rate and sympathetic activity, as shown by reductions in levels of plasma noradrenaline.

Conversely, vasodilators decrease BP and increase sympathetic activity, as shown by increases in both heart rate and plasma levels of noradrenaline. The rate at which BP is lowered determines the sympathetic activation response. Rapid BP reductions with vasodilators produce almost immediate increases in heart rate and levels of circulating catecholamines. This observation is also apparent with different formulations of the Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)- FDA drug.

Thus, intravenous infusions of nifedipine (see Figure 5) produce a rapid reduction in BP and marked reflex tachycardia. These phenomena are rarely apparent in routine practice as BP is scopus researcher assessed at the time of peak drug Prevymis (Letermovir Tablets)- FDA, or in most clinical trials where the focus tends to be on effects at trough at the end of the dosing interval.

However, important differences between drug formulations are apparent in investigations that have focused on effects at the time of peak plasma drug concentrations.

Peak nifedipine plasma concentrations were achieved at four hours after the first dose of the generic MR formulation and at six hours Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)- FDA nifedipine GITS.

Systolic BP decreased rapidly after the first dose of Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)- FDA generic MR formulation, achieving a nadir at five hours post-dose, accompanied by a slight rise in heart rate. After nifedipine GITS, heart rate fell slightly. At the time of peak drug concentration, plasma noradrenaline was higher in patients receiving the generic MR formulation than in those receiving nifedipine GITS and the change from baseline was statistically significantly different.

A similar difference between the drugs was seen again at days 15 and 29, at five hours after switching formulations. After two weeks of treatment the noradrenaline pattern persisted, but was less marked.

Switching between formulations caused opposite effects upon the sympathetic nervous response to falling BP. These acute differences are unlikely to be apparent on single time-point clinic visits, but may lead to clinically important differences in risk for patients. Comparisons of nifedipine retard (slow-release formulation for twice-daily administration) ocean nifedipine GITS demonstrate that, both in first dosing and at steady state, the fluctuating plasma drug concentrations with the MR formulation result in fluctuating BP control and dose-related increases in heart rate.

With nifedipine retard (slow-release formulation for twice-daily administration), plasma levels of noradrenaline Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)- FDA significantly increased both on first dosing jugulare at steady state two to four hours post-dose.

However, there is no evidence of activation of the SNS with the GITS formulation of nifedipine. These findings are supported by a systematic review of the published literature. The same effects are seen Seizalam (Midazolam for Injection)- FDA maintenance therapy with, if anything, greater reductions in BP and greater increases in plasma noradrenaline.

Studies at steady state using the MR formulations of the two drugs produced disparate findings. In contrast, with felodipine extended-release formulation, the BP reduction was more modest but reflex activation was apparent with increases in both heart rate and plasma noradrenaline.

The rate at which plasma concentration (tmax) increases is important, but this parameter is often poorly defined and is not considered as primary in bioequivalence studies. The pharmacokinetics of different once-daily nifedipine formulations are not the same, and thus it is highly unlikely that they have directly similar pharmacodynamic properties. Different formulations of the same dihydropyridine CCB can have negative effects by stimulating the SNS, thereby increasing the potential for adverse events.

Short-acting formulations are associated with sympathetic activation triggered by a more abrupt fall in BP. Thus, considerable caution must be exercised and interchangeability of different formulations cannot be assumed even if clinical or trough BP control seems to be similar.

There is no other rationale for generic drug substitution other than cost savings and thus regulatory authorities must require adequate parameters to ascertain bioequivalence between the generic product and the reference formulation.

The assessment of bioequivalence for MR oral dosage forms in Europe is based upon regulatory guidance. In vitro dissolution data at different pH values may indicate distinct differences between the test and reference formulations. Nifedipine GITS showed identical mean dissolution profiles at different pH values, whereas test formulations may show relevant differences, leading to potential changes in pharmacokinetics in vivo.

It is of utmost importance that the specifications for the in vitro dissolution of the test product should Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)- FDA derived form the dissolution profile of the batch that was found to be bioequivalent to the reference product and would be expected to be similar to those of the reference product. Changes in production site may contribute to relevant differences regarding in vitro dissolution tests.

Usually, a change in the manufacturing site does not require data from an additional bioequivalence study but only from in vitro dissolution tests. These tests are to be performed with the assay method used for quality control for release of production batches. However, in vitro and surface and interface analysis vivo correlation is not requested for the time being. There is further potential for confusion for the prescriber in that some generic nifedipine MR formulations were approved on the basis of pharmacokinetic similarity, others on the basis of pharmacodynamic similarity, i.

Transparency regarding such information is warranted. However, regulatory authorities may not provide such transparency on particular approvals because of confidentiality reasons. This principle is considered true even if a product has a narrow therapeutic index. In contrast, although the Health Canada Therapeutic Products Directorate is responsible for the review of bioequivalence and has responsibility for the issue of a Notice of Compliance (NOC) that assures that the generic is safe, effective and equivalent to a standard reference product, it will not declare that these products are interchangeable.

Thus, the onus rests with the prescriber or pharmacist to make the decision as to whether the patients will obtain equivalent clinical benefit by switching to the alternative dose form. Although some small differences exist between the US Gammagard Liquid (Immune Globulin Intravenous (Human) 10%)- FDA Canada in assessing the bioequivalence of generic drugs, the differences are fundamental in the way that the two countries interpret the data.

The FDA considers their regulations and procedures as sufficiently stringent to guarantee that generic products should provide the same clinical efficacy and safety as the innovator product.



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