Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism

The mobile phase was composed of water/methanol (36/64), ammonium acetate 2mM, and acetic acid synthroid mood 0.1% (v/v). The high‐pressure liquid chromatographic effluent was introduced into a Sciex API‐5000 Tandem Mass Spectrometer equipped with an electrospray ionization source for levothyroxine. Positive ions were detected in the multiple reaction monitoring mode with precursor → product ion pairs of 777.7 m/z → 731.7 m/z or levothyroxine and 783.7 m/z → 737.7 m/z for thyroxine‐13C6. The analytical range of 25‐250 ng/mL had within‐run coefficient of variation (CV) ranging between 1.14% and 2.48% and a between‐run CV ranging between 3.71% and 10.58%. The randomization scheme was not to be available to the bioanalytical division of inVentiv until the clinical and analytical phases had been completed. Thyroid hormones cross the placental barrier to some extent as evidenced by levels in cord blood of athyreotic fetuses being approximately one-third maternal levels.

Utilization and Costs at Follow-Up

The searches in Pubmed and Embase/Medline returned 1217 and 147 publications, respectively. Treatment‐emergent adverse events (TEAEs) were summarized descriptively for all subjects who were dosed (safety population). In the absence of IV injection, the nasogastric route of oral preparation is an alternative for hypothyroid crisis (242). Theoretically, LT4 injections in humans could be administered intravenously, intramuscularly, intra-amniotically, and subcutaneously.

Specific Patient Populations

This article aims to provide a comprehensive review of conventional and novel drug delivery routes and systems. In addition, LT4 absorption and metabolism and the medical conditions that impair the bioavailability of LT4 are also reviewed. Serum TSH levels should be monitored and the SYNTHROID dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the SYNTHROID dosage should return to the pre-pregnancy dose immediately after delivery see Dosage and Administration (2.3).

• Symptoms may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.
• SYNTHROID should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be promptly treated.
• Similar to IM injection, SC injection can serve as a convenient sustained-release system.
• The target level for TSH suppression in these conditions has not been established with controlled studies.

In these patients, levothyroxine therapy should be initiated at lower doses than those recommended in younger individuals or in patients without cardiac disease (see WARNINGS, PRECAUTIONS – Geriatric Use, and DOSAGE AND ADMINISTRATION). If cardiac symptoms develop or worsen, the levothyroxine dose should be reduced or withheld for one week and then cautiously restarted at a lower dose. Overtreatment with levothyroxine sodium may have adverse cardiovascular effects such as an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias.

In addition, alternative routes of LT4 administration have become a new research hotspot. Weekly intramuscular (IM) and subcutaneous (SC) injection represent new methods for sustained drug delivery. The skin, respiratory tract, and oral cavity can also be alternative routes for drug delivery. Moreover, nanomaterials have been used to develop sustained-release drug delivery systems for LT4. Nanomaterials are supposed to eliminate the inconvenience of daily administration and to improve patient compliance.

The main forms of conjugation of T4 produced in the liver are glucuronidation and sulfation. Researchers have also postulated that conjugated T4 could be secreted directly across the bowel wall from the mesenteric circulation (30). The secreted conjugated T4 is then broken down by the intestinal flora and partially reabsorbed (20, 31).

An additional analysis (treatment B vs treatment C) also showed that, when administered without water, the solution was bioequivalent to the capsule. The intrasubject CVs for AUC0 48 and Cmax were low, with values of 8.99% and 8.91%, respectively. Except for patients with specific conditions, such as bedridden individuals needing assistance and people with psychiatric disorders, poor compliance in most patients originates from so-called “human nature,” in other words, forgetfulness. Supervised oral ingestion and a 7-day pillbox are proposed to help (135, 136), but educational booklets have almost no influence on compliance (137). Cappelli et al revealed that liquid LT4 might improve patient compliance compared with tablets (124).

• Plasma carriers facilitate the circulation of drugs, stabilize the molecules, and prevent their renal clearance.
• We anticipate reposting the images once we are able identify and filter out images that do not match the information provided in the drug labels.
• To conclude, thyroid emergencies and inability of oral LT4 are indications for IV administration.
• MG, BN, LW contributed to the design of the study; collected, analyzed, and interpreted the data; and drafted the manuscript.

Patients with Nontoxic Diffuse Goiter or Nodular Thyroid Disease

In the body, thyroid hormone concentration is tightly controlled; intake of small doses of exogenous levothyroxine may cause strong changes in T4 and T3 levels, which in turn could cause profound physiological consequences. To optimize therapy, treatment with levothyroxine requires dose escalation and periodic adjustments 10. As such, the requirements regarding the maximum differences in pharmacokinetic parameters (Cmax and AUC) that can be considered safely have been increased 13. Instead of the commonly accepted bioequivalence margins of 80–125%, for NTI drugs the bioequivalence margin is restrained to 90–111%.

Delays in diagnosis and institution of therapy may have deleterious effects on the child’s intellectual and physical growth and development. Because of the increased prevalence of cardiovascular disease among the elderly, levothyroxine therapy should not be initiated at the full replacement dose (see WARNINGS, PRECAUTIONS , and DOSAGE AND ADMINISTRATION). Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on intellectual development as well as on overall physical growth and maturation. Therefore, SYNTHROID therapy should be initiated immediately upon diagnosis and is generally continued for life. The goal of treatment in pediatric patients with hypothyroidism is to achieve and maintain normal intellectual and physical growth and development. Changes in TBG concentration must be considered when interpreting T4 and T3 values, which necessitates measurement and evaluation of unbound (free) hormone and/or determination of the free T4 index (FT4I).

IV injection is strongly not recommended for long-term treatment due to its rapid and great effect on TH homeostasis. LT4 IV injection can augment the calorigenic effect of norepinephrine within minutes and thus exerts direct, rapid effects on the myocardium, which may lead to cardiac arrest (238). In addition, previous research has shown a positive correlation between the dose of IV LT4 and mortality in patients with myxedema (239). A 3- to 5-day course of IV LT4 with subsequent oral tablets is recommended to prevent potential adverse events and to save costs (240, 241).