SYNTHROID®levothyroxine sodium tablets, USP

Consequently, an in situ implant loaded with 3 mg of LT4 forms in the SC space (Fig. 7E). In vitro experiments revealed a 500-hour gradual release of LT4 after a burst release of ∼20% of the total contents in the first 24 hours. Taking cellular toxicity into consideration, a 50% triblock NMP solution showed the best biocompatibility of all concentrations. However, a 25 °C to 30 °C transition temperature from sol to gel limits the application of thermosensitive polymers in clinical practice. The previous combination of T3 and T4 added a certain dose of T3 tablets while reducing the T4 administration proportionally. Patients had to take more than 1 pill and/or split pills, which inevitably led to confusion and dose variation (156).

1 Important Administration Instructions

Four systematic reviews and meta-analyses based on RCTs failed to show any advantages in quality of life, mood states, or psychometric performance for patients receiving combination therapy (160–163). Although previous meta-analyses reported a preference for combined therapy by patients, a more recent meta-analysis based on 7 blinded RCTs did not support this conclusion (164), suggesting that T3 may serve as a “placebo” and raise patients’ expectations in some nonblinded studies. Taken together, as recommended by the American Thyroid Association, “the use of combined replacement therapy, with the administration of both LT4 and liothyronine (LT3), is generally not recommended due to the low quality of the available evidence. A trial may be considered in those patients with normal values of serum TSH who continue to complain of symptoms of hypothyroidism. Also, in these cases, the presence of coexistent nonthyroid problems should be first ruled out” (44). We further recommend discussing the financial burdens with these patients while addressing concomitant diseases and mitigating their unrealistic expectations.

• A UFLC chromatograph (Shimadzu) coupled to a Qtrap 5500 mass spectrometer (ABSciex) was used.
• Proton pump inhibitors reduce the acidity (and increase the pH) of the stomach, and thus may reduce the bioavailability of LT4 by about 40% 29; conversely, co-administration of ascorbic acid (vitamin C) reduces gastric pH and increases the absorption of LT4 29, 30.
• In children in whom a diagnosis of permanent hypothyroidism has not been established, it is recommended that levothyroxine administration be discontinued for a 30-day trial period, but only after the child is at least 3 years of age.
• All participating subjects were judged eligible for the study when assessed against the inclusion and exclusion criteria.
• The dose used in the study of 600 μg of levothyroxine allowed one to identify the exogenous supply of this synthetic hormone and to differentiate it from the endogenous production.

2 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease

Published studies report that levothyroxine is present in human milk following the administration of oral levothyroxine. No adverse effects on the breastfed infant have been reported and there is no information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers with low milk supply. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYNTHROID and any potential adverse effects on the breastfed infant from SYNTHROID or from the underlying maternal condition.

Therefore, measurements of only T4 may be insufficient to explain changes in elderly patients’ thyroid function. Pregnancy tests were performed for all women at screening, before dosing in each period, and for study exit procedures. Clinical laboratory tests (biochemistry, hematology, endocrinology, and urinalysis) were performed for each subject at the time of screening, before dosing of periods 2 and 3, and for study exit procedures. In addition, endocrinology tests were performed at the safety return visit, which occurred approximately 1 month following the last dose of levothyroxine. Physical examinations were performed at the time of screening procedures and before dosing of periods 2 and 3. ECG measurements were performed at the time of screening, before dosing and approximately 48hours postdose in each period and at study exit.

Over-treatment with levothyroxine may cause an increase in heart rate, cardiac wall thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with cardiovascular disease and in elderly patients. Initiate SYNTHROID therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease see Dosage and Administration (2.3) and Use in Specific Populations (8.5). For pregnant patients with pre-existing hypothyroidism, measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each trimester of pregnancy. In pregnant patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range. For adult patients with primary hypothyroidism, titrate until the patient is clinically euthyroid and the serum TSH returns to normal see Dosage and Administration (2.3). Secondary outcomes included all-cause and hypothyroidism-related healthcare resource utilization (HCRU) and costs.

The reason for such a restriction arises, in part, from the observation that these NTI drugs have low within-subject variability coefficients (usually below 10%). Accordingly, the estimated sample size for demonstrating bioequivalence in a two-sequence, two-period crossover study requires testing in a reasonable number of volunteers, usually 24 up to 36 volunteers. Lots of medications, food and beverages have been reported to impair the bioavailability of levothyroxine. The proposed mechanisms of drugs interaction include direct complexing, alkalization, acceleration of catabolism or deiodination, etc. Although the classes of drugs are various, clinical practitioners should be aware plavix synthroid that discontinuation or administration separation can suppress TSH in most cases. Liquid formulations (solution and soft-gel capsules) can be used in malabsorption induced by complexing and alkalization.

The elimination half-life of LT4 after oral dosing averages 7.5 days in patients with hypothyroidism, consistent with once-daily dosing 14. A slightly lower elimination half-life was reported in euthyroid subjects (average 6.2 days) 14. Interestingly, the elimination half-life of T3 is much lower (1–1.4 days, on average) 14, which may complicate future attempts to deliver LT4–T3 combination therapies 22. This minimises the effect of endogenous concentrations on bioequivalence assessments182,184 by ensuring a high signal (concentrations related to exogenous levothyroxine) to noise (endogenous levels) ratio. Although thyroid hormones are excreted only minimally in human milk, caution should be exercised when SYNTHROID is administered to a nursing woman. However, adequate replacement doses of levothyroxine are generally needed to maintain normal lactation.

Administration and Pharmacokinetics of Levothyroxine

An intrasubject variability of 18.27% was observed for Cmax and an intrasubject variability of 26.19% for AUC. Both formulations have the same pharmacokinetic profile and are bioequivalent in the narrow therapeutic index required by some health authorities. Chitosan has been a hotspot in recent years due to its unique properties, such as biocompatibility, biodegradability, safety, and mucoadhesivity. Rostami et al encapsulated LT4 with chitosan nanoparticles at an average diameter of 220 nm (277).

Subjects and Methods

Persistent hypothyroidism can also be induced by noninterchangeability between formulations and poor compliance. Novel formulations (liquid solutions and soft gel capsules) have been designed to eliminate malabsorption. Some other delivery routes (injections, suppositories, sprays, and sublingual and transdermal administrations) are aimed at circumventing different difficulties in dosing, such as thyroid emergencies and dysphagia. Moreover, nanomaterials have been used to develop delivery systems for the sustained release of levothyroxine to improve patient compliance and reduce costs.

• Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and SYNTHROID may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.
• Moreover, increased inactivation of LT4 via the monodeiodinase induced by mifepristone, rifampicin, and carbamazepine can reduce the T1/2 of LT4 (86–88).
• 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).
• A study has been conducted to compare the bioavailability of levothyroxine sodium oral solution and levothyroxine sodium soft capsule in healthy volunteers under fasting conditions.
• Overtreatment or undertreatment with SYNTHROID may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, gastrointestinal function, and glucose and lipid metabolism in adult or pediatric patients.

This phenomenon is assumed to be attributed to a low level of circulating T3, which plays a superior role to T4 in the feedback of the hypothalamus–pituitary–thyroid axis (144). A previous study showed a 10% to 20% reduction in serum T3 levels in ∼1.8 thousand LT4-treated hypothyroid patients compared with the healthy population (145). Similar phenomena were also observed in thyroidectomized rats, which reached euthyroidism only after normalization of serum T3 levels (146). Interestingly, although there are many studies on the interaction between PPIs and LT4, only one case report has been published.33 The female patients dosed LT4 due to Hashimoto’s thyroiditis. Her TSH level rose above the reference range when she began dosing 40 mg/day of omeprazole. The hypothyroid symptoms resolved and the TSH dropped after she switched LT4 tablets to soft-gel capsules without dose adjustment.