NO-Generic and brand-name L-thyroxine are not bioequivalent for children with severe congenital hypothyroidism.Carswell JM, Gordon JH, Popovsky E, Hale A, Brown RS. J Clin Endocrinol Metab. 2013 Feb;98(2):610-7. doi: 10.1210/jc.2012-3125.
In the United States, generic substitution of levothyroxine (l-T(4)) by pharmacists is permitted if the formulations are deemed to be bioequivalent by the Federal Drug Administration, but there is widespread concern that the pharmacokinetic standard used is too insensitive. We aimed to evaluate the bioequivalence of a brand-name l-T(4) (Synthroid) and an AB-rated generic formulation (Sandoz, Princeton, NJ) in children with severe hypothyroidism. This was a prospective randomized crossover study in which patients received 8 weeks of one l-T(4) formulation followed by 8 weeks of the other. The setting was an academic medical center. Of 31 children with an initial serum TSH concentration >100 mU/L, 20 had congenital hypothyroidism (CH), and 11 had autoimmune thyroiditis. The primary endpoint was the serum TSH concentration. Secondary endpoints were the free T(4) and total T(3) concentrations.
: The serum TSH concentration was significantly lower after 8 weeks of Synthroid than after generic drug (P = .002), but thyroid hormone levels did not differ significantly. Subgroup analysis revealed that the difference in TSH was restricted to patients with CH (P = .0005). Patients with CH required a higher l-T(4) dose (P < .0004) and were younger (P = .003) but were not resistant to thyroid hormone; 15 of 16 CH patients had severe thyroid dysgenesis or agenesis on imaging. The response to generic vs brand-name preparation remained significant when adjusted for age.
Synthroid and an AB-rated generic l-T(4) are not bioequivalent for patients with severe hypothyroidism due to CH, probably because of diminished thyroid reserve. It would therefore seem prudent not to substitute l-T(4) formulations in patients with severe CH, particularly in those <3 yr of age. Our results may have important implications for other severely hypothyroid patients in whom precise titration of l-T(4) is necessary
MAYBE-Generic levothyroxine compared with synthroid in young children with congenital hypothyroidism.Lomenick JP, Wang L, Ampah SB, Saville BR, Greenwald FI. J Clin Endocrinol Metab. 2013 Feb;98(2):653-8. doi: 10.1210/jc.2012-3558.
Clinicians who prescribe levothyroxine (LT4) for hypothyroidism often feel strongly about using a brand-name drug instead of a generic. The objective of the study was to determine whether Synthroid resulted in better control of congenital hypothyroidism than generic LT4. Design: This was a 5-year retrospective study: The study was conducted at 1 tertiary care center.: Children who were 0-36 months old with congenital hypothyroidism followed up at our center from 2006 to 2011 were treated with either Synthroid exclusively (35 subjects) or generic LT4 exclusively (27 subjects). We recorded the subjects’ TSH and free T(4) measurements, how often their LT4 dose was adjusted, and the duration of follow-up. TSH variance between the groups was measured. Secondary end points were the frequency of LT4 dose changes and the variance in free T(4).:
Using the Wilcoxon rank sum test, there was no difference in TSH SD in the Synthroid group compared with the generic group (median 3.0 vs 2.2, P = .27). Using a linear mixed model, children treated with the generic LT4 had lower TSH estimated SD [1.35 with 95% confidence interval (CI) (1.194, 1.526)] than the Synthroid group [1.66 with 95% CI (1.536, 1.803)]. Similarly, no difference was observed in free T(4) SD between the groups using the Wilcoxon rank sum test (median 0.29 generic vs 0.36 Synthroid, P = .11), but the generic group had lower free T(4) estimated SD than the Synthroid group using the linear mixed model [0.216 with 95% CI (0.187, 0.249) vs 0.298 with 95% CI (0.273,0.326)]. Frequency of LT4 dosing adjustments was similar between the groups, both in total (median 2.0 for generic vs 3.0 for Synthroid, P = .097) and when adjusted for number of TSH checks (ratio 0.25 generic vs 0.31 Synthroid, P = .45).
: In our study of congenital hypothyroidism, generic LT4 treatment resulted in similar or better control of hypothyroidism compared with Synthroid, as assessed by the clinical outcomes of TSH variance and the frequency of LT4 dosing adjustments
COMMENT- first study seems to clearly show that the generic T4 used did not have exactly “equivalent “ biologic potency to the brand product in a prospective, randomized, cross-over, 8 week period study, although certainly both were effective therapy. The second study was not a comparison of biologic equivalence, but was a non-randomized retrospective comparison of treatment groups, shoswing equivalent clinical effficacy for a generic and the branded product over a 5 year term. Perhaps the message from both is that if your patient always receives the same brand of T4 with each refill, a consistent clinical response can be expected. L De Groot, MD