Levothyroxine: Conventional and Novel Drug Delivery Formulations

Giardiasis and Enterobius vermicularis can damage intestinal mucosal cells and subsequently decrease LT4 absorption (23, 56). Notably, critically ill patients may exhibit reduced intestinal absorption of LT4 and increased conversion of T4 to rT3, regardless of the causes of the critical illness (57). Some other intestinal dysfunctions, such as intestinal lymphangiectasia and ulcerative colitis, have been revealed to cause impaired LT4 absorption, although the underlying mechanisms remain unclear (58, 59). TSH may not normalize in some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid feedback. Failure of the serum T4 to increase into the upper half of the normal range within 2 weeks of initiation of SYNTHROID therapy and/or of the serum TSH to decrease below 20 mIU per liter within 4 weeks may indicate the patient is not receiving adequate therapy. Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of SYNTHROID see Warnings and Precautions (5.1)and Use in Specific Populations (8.4).

Effects on Bone Mineral Density

Stop biotin and biotin-containing supplements for at least 2 days before assessing TSH and/or T4 levels see Drug Interactions (7.10). Start at a lower starting dosage and increase the dosage every 4 to 6 weeks as needed based on clinical and laboratory response. To be included in the study, patients were required to have at least two distinct claims between 1 January 2006 and 31 December 2017 with ICD-9/10-CM diagnosis codes for hypothyroidism (see Supplementary Material Table 1). Patients were also required to have two or more fills for either Synthroid or GL (same or multiple).

Protein Binding

In vitro release in phosphate saline buffer revealed a 0-order profile in 15 to 20 hours. Interestingly, energy applied from the outside, such as ultrasound, could accelerate the liberation of LT4 from polymers. You are encouraged to report negative side effects of prescription drugs to the FDA.

Recent studies also supported the superiority of solution and soft-gel capsules over tablets when taken with food and coffee.99,100,112–117 From a clinical standpoint, clinicians could recommend novel formulations to those who have difficulty taking drugs on empty stomachs. The aim of that study was to assess the bioequivalence between levothyroxine oral solution contained in unit‐dose ampules diluted in water and a reference levothyroxine capsule under fasting conditions. It was demonstrated in that study that levothyroxine oral solution was bioequivalent when diluted in water to the capsule formulation. The rate and extent of absorption of the new solution were also evaluated when administered on dilution in water or directly into the mouth without water. This study has also shown that the levothyroxine solution can be administered directly into the mouth from the unit‐dose ampule because this mode of administration does not change the rate and extent of absorption of levothyroxine. Exercise caution when administering levothyroxine to patients with cardiovascular disorders and to the elderly in whom there is an increased risk of occult cardiac disease.

• A new formulation of levothyroxine sodium has been developed in the form of an oral solution contained in unit‐dose ampules.
• For levothyroxine, however, since bioequivalence requires comparability of baseline-subtracted pharmacokinetic parameters, variability has been reported in some cases to exceed 20% for intrasubject coefficient of variation 2.
• The compounds were then eluted with 400 μL of methanol/ammonium hydroxide (95/5).
• If so, advise them to stop biotin supplementation at least 2 days before assessing TSH and/or T4 levels see Dosage and Administration (2.4) and Drug Interactions (7.10).

In hypothyroid patients who are suspected of having drug interactions, the diagnosis of malabsorption entails a comprehensive medical history taking. Any diet change or drug used before the increase in TSH levels should be thoroughly investigated. Clinicians should also be alert for frequently prescribed agents interfering with LT4, such as calcium and iron supplements, PPIs, statins, and hypoglycemics.

In adult patients with primary (thyroidal) hypothyroidism, serum TSH levels (using a sensitive assay) alone may be used to monitor therapy. The frequency of TSH monitoring during levothyroxine dose titration depends on the clinical situation but it is generally recommended at 6-8 week intervals until normalization. For patients who have recently initiated levothyroxine therapy and whose serum TSH has normalized or in patients who have had their dosage or brand of levothyroxine changed, the serum TSH concentration should be measured after 8-12 weeks. When the optimum replacement dose has been attained, clinical (physical examination) and biochemical monitoring may be performed every 6-12 months, depending on the clinical situation, and whenever there is a change in the patient’s status. It is recommended that a physical examination and a serum TSH measurement be performed at least annually in patients receiving SYNTHROID (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION). Many concomitant diseases or conditions have been reported to interfere with the efficacy of oral or nonoral LT4 (Fig. 3).

• Similarly, gastric sleeve surgery and other bariatric surgery can cause malabsorption in some LT4-treated patients (49).
• The statistical analyses were performed using SAS Enterprise Guide 7.1 (SAS Institute Inc., Cary, NC, USA, 2014).
• As revealed by a meta-analysis by Laurent et al (219) based on 8 prospective or randomized controlled studies, reduced TSH levels were observed in patients with malabsorption who were taking liquid formulations.
• A 10 to 150 µg/kg/day dose via IA injection at an interval of 1 to 4 weeks is recommended, depending on the goiter sizes and fetal serum TH levels (250, 254, 255).

Absorption

Administer synthroid morphine SYNTHROID to pediatric patients who cannot swallow intact tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 mL) of water and immediately administering the suspension by spoon or dropper. Do not administer in foods that decrease absorption of SYNTHROID, such as soybean-based infant formula see Drug Interactions (7.9). SYNTHROID is indicated in adult and pediatric patients, including neonates, as a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. A randomised clinical trial compared the clinical pharmacokinetics of a new formulation of LT4 that meets these updated, narrowed requirements for bioequivalence with the previous formulation, in 216 healthy subjects 11, 56. 1 showed that the plasma concentration-time curves and Cmax values of the two formulations were essentially identical 11.

Moreover, the administration of levothyroxine oral solution without water did not affect the rate and extent of its absorption. In conclusion, levothyroxine oral solution unit-dose ampules were bioequivalent to the levothyroxine capsule when administered with or without water. A new formulation of levothyroxine sodium has been developed in the form of an oral solution contained in unit‐dose ampules.

Limitations of Included Articles

SYNTHROID may be administered to infants and children who cannot swallow intact tablets by crushing the tablet and suspending the freshly crushed tablet in a small amount (5-10 mL or 1-2 teaspoons) of water. Foods that decrease absorption of levothyroxine, such as soybean infant formula, should not be used for administering levothyroxine sodium tablets (see PRECAUTIONS – Drug-Food Interactions). Regardless of the indication for use, careful dosage titration is necessary to avoid the consequences of over- or under-treatment. These consequences include, among others, effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, gastrointestinal function, and on glucose and lipid metabolism. Many drugs interact with levothyroxine sodium necessitating adjustments in dosing to maintain therapeutic response (see Drug Interactions ).

A web-based survey of Italian endocrinologists also supported the prescription of liquid LT4 for patients (3) with unexplained poor biochemical control of hypothyroidism (147). From a clinical standpoint, we also recommend the prescription of liquid LT4 for patients (4) with difficulty swallowing. Malabsorption of LT4 results in lower than expected blood levels of LT4 and higher than expected levels of TSH, sometimes even in the setting of high doses of exogenous LT4. Alternative formulations to the usual tablet may be considered for patients with documented LT4 malabsorption 27, 31. In cases where suboptimal adherence to LT4 therapy is suspected 32, the LT4 absorption test, where thyroid hormone levels are measured after a supervised dose of LT4, can be useful in distinguishing non-adherence of LT4 from genuine cases of malabsorption of LT4 33. Intramuscular LT4 treatment has been proposed for patients with severe intestinal malabsorption of LT4 though this approach remains within the research domain at present 34.