Levothyroxine
| Evidence Level: L4 | Predicted Indications: 10 |
Table of Contents
Levothyroxine: From Thyroid Hormone Replacement to Endemic Goiter
One-Sentence Summary
Levothyroxine is a synthetic thyroid hormone marketed in the United States as tablets and as a lyophilized injection. The Evidence Pack does not list an approved indication for it. The TxGNN model predicts it may be effective for endemic goiter, but only 1 clinical trial (unrelated to levothyroxine) and 18 mostly indirect publications are retrieved. Evidence is weak: none of the retrieved literature is a trial of levothyroxine for this indication, so this is best treated as a research question.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not listed in the retrieved US label data (thyroid hormone replacement product) |
| Predicted New Indication | Endemic goiter |
| TxGNN Prediction Score | 99.81% |
| Evidence Level | L4 |
| US Market Status | ✓ Marketed |
| Number of NDAs | 20 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the Evidence Pack. Levothyroxine is a thyroid hormone replacement, and the following is a plausible mechanistic rationale rather than a documented finding.
Endemic goiter arises mainly from iodine deficiency. Low thyroid hormone output raises TSH, and TSH drives thyroid growth. Giving thyroid hormone could lower TSH and limit that growth.
The retrieved literature is largely about iodine deficiency, epidemiology and iodine prophylaxis, not levothyroxine treatment. Iodine repletion remains the etiologic first-line approach. The high TxGNN score is therefore supported only by indirect evidence.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT04482907 | NA | Completed | 68 | Dill (Anethum graveolens) vs placebo for 90 days in thyroiditis and nodular goiter. Not a levothyroxine study and not an endemic goiter population, so low relevance. |
Literature Evidence
None of these papers is a randomized trial of levothyroxine in endemic goiter. The one direct levothyroxine study (PMID 3278876) is listed first.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 3278876 | 1988 | Multicenter treatment study (not classified in pack) | Dtsch Med Wochenschr | 74 patients with diffuse endemic goiter got levothyroxine 150 µg/day or levothyroxine 100 µg plus iodide for 6 months, followed by iodide prophylaxis. The abstract is truncated, so goiter-reduction results are not available. |
| 2031356 | 1991 | Review | World J Surg | Iodine deficiency is the primary cause of endemic goiter. Iodine prophylaxis programs face technical and socioeconomic difficulties. |
| 7704809 | 1994 | Review | Curr Ther Endocrinol Metab | General review of endemic goiter (no abstract available). |
| 36839362 | 2023 | Review | Nutrients | Overview of iodine deficiency and prophylaxis. Supports iodine repletion, not levothyroxine, as the primary approach. |
| 25629792 | 2015 | Intervention study (iodine) | Curr Med Res Opin | 460 pregnant women; maternal iodine supplementation in goiter-endemic areas and its effect on thyroid function and birth outcome. |
| 6309889 | 1983 | Cohort | J Clin Endocrinol Metab | 58 goitrous patients given iodized oil. Goiter size decreased. Serum T4 stayed roughly constant. |
| 6304776 | 1983 | Cohort | Prog Clin Biol Res | TSH is higher in endemic goiter patients and rises as iodine intake falls. This supports the TSH-driven growth rationale. |
| 8121602 | 1993 | Case series (not classified in pack) | Minerva Ginecol | 38 pregnant women with endemic goiter; 4 received L-thyroxine 50–100 µg/day. The goiter enlarged in 42% of the women. |
| 4312017 | 1969 | Intervention study (iodized oil) | Am J Clin Nutr | Prophylaxis and treatment of endemic goiter with iodized oil in Ecuador and Peru. |
| 4310499 | 1969 | Not classified | J Clin Endocrinol Metab | Prophylaxis and treatment of endemic goiter in Peru with iodized oil. |
US Market Information
The retrieved records contain no approved-indication text. Five of the 20 authorizations are shown.
| Authorization Number | Product Name | Dosage Form | Manufacturer |
|---|---|---|---|
| NDA021116 | levothyroxine sodium | Tablet | Preferred Pharmaceuticals, Inc. |
| ANDA216729 | Levothyroxine Sodium | Injection, powder, lyophilized, for solution | ONESOURCE SPECIALTY PHARMA LIMITED |
| NDA202231 | Levothyroxine Sodium | Injection, powder, lyophilized, for solution | Fresenius Kabi USA, LLC |
| ANDA208749 | Levothyroxine Sodium | Injection, powder, lyophilized, for solution | Sagent Pharmaceuticals |
| NDA021402 | Synthroid | Tablet | AbbVie Inc. |
Safety Considerations
Please refer to the package insert for safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The 99.81% TxGNN score is supported only by indirect evidence. The single retrieved trial tests dill, not levothyroxine, and the literature centers on iodine as the standard approach. Levothyroxine’s TSH-suppression rationale is plausible, but nothing retrieved shows it works in endemic goiter.
To proceed, the following is needed:
- Full text of the 1988 multicenter study (PMID 3278876) to extract goiter-volume outcomes for levothyroxine, with or without iodide.
- A targeted search for randomized trials of levothyroxine versus iodine in iodine-deficient populations.
- FDA package insert warnings and contraindications, and mechanism of action data.
- A safety plan against iatrogenic hyperthyroidism (TSH monitoring, cardiac and bone risk).
Two related predicted indications have stronger support and may be a better place to start:
- Nodular goiter (rank 3): a large Phase 4 placebo-controlled trial (NCT00277589, n=1,024) and a randomized post-lobectomy levothyroxine trial (NCT00941551, n=150). The levothyroxine arm of NCT00277589 still needs to be verified against the registry record.
- Nontoxic goiter (rank 8): a randomized trial of levothyroxine versus radioactive iodine (PMID 11238476).
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.