Levothyroxine

H03A - Thyroid preparations ATC H03AA01 Small molecule approved 1982 Oral Parenteral Natural product Narrow therapeutic index Black-box warning

JFDA label: Euthyrox 50mcg tab

⚠ Black-Box Warning

Weight reduction:

Mechanism of Action

Levothyroxine (T4) is a synthetic form of thyroxine, an endogenous hormone secreted by the thyroid gland. T4 is converted to its active metabolite, L-triiodothyronine (T3). Thyroid hormones (T4 and T3) then bind to thyroid receptor proteins in the cell nucleus and exert metabolic effects through control of DNA transcription and protein synthesis; involved in normal metabolism, growth, and development; promotes gluconeogenesis, increases utilization and mobilization of glycogen stores, and stimulates protein synthesis, increases basal metabolic rate

Indications

Approved

Hypothyroidism
Injectable
Oral
Pituitary thyrotropin-stimulating hormone suppression

Off-label

Cadaveric organ recovery (hormonal resuscitation)
Subclinical hypothyroidism

Contraindications

Source: Lexicomp

Injection: There are no contraindications listed in the manufacturer's labeling when used for labeled indication (treatment of myxedema coma) Absolute
Note: Product labels may vary Absolute
also consult product labels. Reported hypersensitivity to levothyroxine or any component of the formulation is not considered an absolute contraindication (Jonklass 2014) Absolute
consider contraindications for oral therapy if using as a temporary substitute for oral treatment (off-label use) in patients with chronic hypothyroidism. Oral: Uncorrected adrenal insufficiency Absolute
refer to Warnings/Precautions Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (13)

Common Palpitations (dose-related) · Tachycardia (dose-related)

Uncommon Atrial fibrillation (over-replacement)

Not Known Angina pectoris · cardiac arrest · cardiac arrhythmia · cardiac failure · flushing · hypertension · increased pulse · myocardial infarction · palpitations · tachycardia

Nervous system disorders (14)

Common Headache

Not Known Anxiety · choking sensation (Levoxyl) · emotional lability · fatigue · headache · heat intolerance · hyperactivity · insomnia · irritability · myasthenia · nervousness · pseudotumor cerebri (children) · seizure (rare)

Hepatobiliary disorders (1)

Not Known Increased liver enzymes

Renal and urinary disorders (1)

Not Known Infertility

Immune system disorders (1)

Not Known Hypersensitivity (to inactive ingredients; symptoms include urticaria, pruritus, rash, flushing, angioedema, GI symptoms, fever, arthralgia, serum sickness, wheezing)

Metabolism and nutrition disorders (3)

Common Weight loss (dose-related)

Not Known Menstrual disease · weight loss

Gastrointestinal disorders (6)

Not Known Abdominal cramps · diarrhea · dysphagia (Levoxyl) · gag reflex (Levoxyl) · increased appetite · vomiting

Skin and subcutaneous tissue disorders (3)

Rare Allergic skin reactions

Not Known Alopecia · diaphoresis

Musculoskeletal and connective tissue disorders (4)

Uncommon Osteoporosis (long-term over-replacement)

Not Known Decreased bone mineral density · slipped capital femoral epiphysis (children) · tremor

Psychiatric disorders (1)

Common Insomnia (dose-related)

General disorders and administration site conditions (2)

Common Heat intolerance

Not Known Fever

Respiratory, thoracic and mediastinal disorders (1)

Not Known Dyspnea

Dosing

Source: Lexicomp

Doses should be adjusted based on clinical response and laboratory parameters. Hypothyroidism: Oral: Adults (healthy) who have been hypothyroid for only a few months: Initial: 1.6 mcg/kg/day; adjust dose by 12.5 to 25 mcg/day every 4 to 6 weeks as needed. Usual doses are ≤200 mcg/day (range: 100 to 125 mcg/day [70 kg adult]); doses ≥300 mcg/day are rare (consider poor compliance, malabsorption, and/or drug interactions). Adults >50 years of age without evidence of coronary heart disease (off-label): Lower starting doses (eg, 50 mcg/day) may be preferred (ATA/AACE [Garber 2012]). Adults with cardiac disease: Initial: 12.5 to 25 mcg/day; adjust dose by 12.5 to 25 mcg increments at 6- to 8-week intervals as needed Adults with severe longstanding hypothyroidism: Initial: 12.5 to 25 mcg/day; adjust dose by 12.5 to 25 mcg/day every 2 to 4 weeks as appropriate Pregnant patients: Dosage requirements may increase during pregnancy in patients with preexisting disease. If new onset hypothyroidism occurs initiate therapy with 1.6 mcg/kg/day (for severe hypothyroidism) or 1 mcg/kg/day (for mild hypothyroidism [TSH IM, IV (off-label route [IM] and off-label use): ~75% of the oral dose by IV administration (ATA [Jonklaas 2014]); alternatively 50% of the previously established oral dose by IV or IM administration has been recommended (Levothyroxine injection Canadian product labeling 2017). Note: Bioavailability of the oral formulation is highly variable, but absorption has been measured to be ~80%, when the oral tablet formulation was administered in the recommended fasting state (Dickerson 2010; Fish 1987). TSH suppression: Oral: Well-differentiated thyroid cancer (papillary and follicular): Highly individualized; Doses >2 mcg/kg/day may be needed to suppress TSH to Benign nodules and nontoxic multinodular goiter: Routine use of T4 for TSH suppression is not recommended in patients with benign thyroid nodules. In patients deemed appropriate candidates, treatment should never be fully suppressive (TSH Myxedema coma or stupor: IV: 300 to 500 mcg initially, followed by 50 to 100 mcg once daily until patient is able to tolerate oral administration; smaller doses should be considered in patients with cardiovascular disease Alternate recommendations (off-label dose): Initial loading dose: 200 to 400 mcg; followed by a daily replacement dose of 1.2 mcg/kg/day (which is 75% of the 1.6 mcg/kg oral daily replacement dose reduced for IV administration); smaller doses should be considered for smaller or older patients and those with a history of coronary disease or arrhythmia; institute oral therapy after the patient improves clinically (ATA [Jonklaas 2014]) Cadaveric organ recovery (hormonal resuscitation) (off-label use): IV: Initial: 20 mcg bolus followed by a continuous infusion of 10 mcg/hour administered to the brain-dead donor who is hemodynamically unstable requiring significant vasopressor support; give concomitantly with methylprednisolone, dextrose, and regular

(For additional information see "Levothyroxine: Pediatric drug information") Hypothyroidism (acquired or congenital): Infants, Children, and Adolescents: Doses should be adjusted based on clinical response and laboratory parameters; on a weight basis, dosing is higher in infants and children than adults due to the higher metabolic clearance. Capsules are approved for use in children ≥6 years of age and adolescents. Note: Hyperactivity in older children may be minimized by starting at 25% of the recommended dose and increasing each week by that amount until the full dose is achieved (4 weeks). Oral: Daily dosage based on body weight and age as listed below: 1 to 3 months: 10 to 15 mcg/kg/dose once daily; in severe cases of hypothyroidism (serum T4 >3 months of age to 6 months: 8 to 10 mcg/kg/dose once daily >6 months of age to 12 months: 6 to 8 mcg/kg/dose once daily 1 to 5 years: 5 to 6 mcg/kg/dose once daily 6 to 12 years: 4 to 5 mcg/kg/dose once daily >12 years of age but growth and puberty incomplete: 2 to 3 mcg/kg/dose once daily Adolescents with growth and puberty complete: 1.6 mcg/kg/day; refer to adult dosing Patient with cardiac disease: Note: Lower initial doses are recommended. Infants and Children: Initial: ~50% of target replacement dose; increase after 2 weeks based on free thyroxine levels (Leger 2014) Adolescents with growth and puberty complete: Initial: 12.5 to 25 mcg/day; adjust dose by 12.5 to 25 mcg increments at 6- to 8-week intervals as needed IV: Note: The relative bioavailability of injectable and oral levothyroxine has not been established; use caution when switching patients from oral to IV as accurate dosing conversions have not been established. Infants, Children, and Adolescents: ~75% to 80% of the oral dose has been suggested (ATA [Jonklaas 2014]; Leger 2014)

Doses should be adjusted based on clinical response and laboratory parameters. Hypothyroidism: Oral: Initial: 12.5 to 25 mcg/day; adjust dose every 6 to 8 weeks until euthyroid. Elderly patients may only require Myxedema coma: Refer to adult dosing; lower doses may be needed. Subclinical hypothyroidism (if treated) (off-label use): Oral: Initial dosing is generally lower than that required in the treatment of overt hypothyroidism; higher serum TSH targets may be appropriate in elderly patients (ATA/AACE [Garber 2012])

There are no dosage adjustments provided in the manufacturer's labeling.

Warnings & Precautions

Source: Lexicomp

Adrenal insufficiency

Use with caution in patients with adrenal insufficiency; symptoms may be exaggerated or aggravated. Treatment with glucocorticoids should precede levothyroxine therapy in patients with adrenal insufficiency. Use is contraindicated in patients with uncorrected adrenal insufficiency.

Benign thyroid nodules

Appropriate use: Routine use of T4 for thyroid stimulating hormone (TSH) suppression is not recommended in patients with benign thyroid nodules. Treatment should never be fully suppressive (TSH - Use of T4 may be considered in association with iodine supplementation only in young patients residing in iodine-deficient areas with small thyroid nodules and no evidence of functional autonomy (AACE/ACE/AME [Gharib 2016]). - Use should be avoided in postmenopausal women, elderly patients, patients with cardiovascular disease, osteoporosis, large thyroid nodules or long-standing goiters, or low-normal TSH levels (AACE/ACE/AME [Gharib 2016]).

Cardiovascular disease

Use with caution and reduce dosage in patients with cardiovascular disease; patients with developing or worsening cardiac symptoms should have their dose reduced or therapy withheld for 7 days and then resumed at a reduced dose. Chronic hypothyroidism predisposes patients to coronary artery disease; monitor patients closely for development of cardiac ischemia. Similarly, patients with heart failure and hypothyroidism should be closely followed.

Diabetes

Use with caution in patients with diabetes mellitus (may worsen glycemic control) and diabetes insipidus (thyroid hormone increases glomerular filtration rate and downregulates aquaporin channels in the renal tubules, which could affect urinary output) (Mariani 2012).

Osteoporosis

Long-term therapy can decrease bone mineral density. Postmenopausal women and women using suppressive doses should receive the lowest dose necessary for clinical response. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Elderly

Use with caution; suppressed TSH levels may increase risk of atrial fibrillation and mortality secondary to cardiovascular disease (Gharib 2016; Parle 2001). Increase dose slowly and monitor for signs/symptoms of angina. Dosage form specific issues:

Levoxyl

Product may rapidly swell and disintegrate, causing choking or gagging (should be administered with a full glass of water); use caution in patients with dysphagia or other swallowing disorders.

Product interchangeability

Switching between different levothyroxine products may result in variations in the administered dose and altered TSH values and is not generally recommended; if formulations are changed, close monitoring of TSH is recommended (ATA [Jonklaas 2014]). Pediatric patients with congenital hypothyroidism may be more sensitive to changes in formulation (Carswell 2013). Other warnings/precautions:

Hypersensitivity

Patients with reported hypersensitivity to levothyroxine may be managed with dose reductions and slow titration, by switching formulations or products, or referral to an allergist (Jonklaas 2014).

Weight reduction (off-label use)

Thyroid supplements are ineffective and potentially toxic when used for the treatment of obesity or for weight reduction, especially in euthyroid patients. High doses may produce serious or even life-threatening toxic effects, particularly when used with some anorectic drugs (eg, sympathomimetic amines). Levothyroxine, either alone or with other concomitant therapeutic agents, should not be used for the treatment of obesity or for weight loss.

Pregnancy & Lactation

Pregnancy

FDA category A

Safe

Inadequately treated hypothyroidism more dangerous than drug itself. Monitor TSH every 4–6 weeks; increase dose proactively on pregnancy confirmation (many women need 25–30% dose increase)

Lactation

Endogenous thyroid hormones are minimally found in breast milk. The manufacturer recommends that caution be used if administered to a nursing woman. The amount of endogenous thyroxine found in breast milk does not influence infant plasma thyroid values (van Wassenaer 2002). Levothyroxine was not found to cause adverse events to the infant or mother during breastfeeding (Ito 1993). Adequate thyroid hormone concentrations are required to maintain normal lactation. Appropriate levothyroxine doses

Monitoring

Efficacy	TSH (every 6–12 weeks after dose change, then annually); free T4; clinical symptoms (fatigue, weight, heart rate)
Toxicity	Symptoms of over-replacement (palpitations, weight loss, heat intolerance, osteoporosis risk); TSH < 0.1 mIU/L sustained → atrial fibrillation and osteoporosis risk
Clinical pearl	TSH is the most sensitive marker of thyroid hormone adequacy. However, some patients feel better with TSH in the lower half of normal range. Annual monitoring is sufficient when stable.
Counseling	Take on an empty stomach 30–60 min before breakfast. Many drugs reduce absorption (calcium, iron, antacids, proton pump inhibitors) — separate by 4 h. Do not change brands without discussion.

Chemistry & Properties

Formula	C15H11I4NO4
Molecular weight	776.87 g/mol
IUPAC name	(2S)-2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid
CAS	51-48-9
PubChem CID	5819
InChIKey	`XUIIKFGFIJCVMT-LBPRGKRZSA-N`
logP	4.56 (XLogP 2.4)
Polar surface area	92.78 Å²
H-bond acceptors / donors	4 / 3
Drug-likeness (QED)	0.39
Lipinski violations	1

SMILES

N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP2C9	Inhibitor	—
CYP2C9	Substrate	—
CYP2D6	Substrate	—
CYP3A4	Substrate	—

Receptor binding (top 1)

Target	Action	Affinity
Thyroid hormone receptor-β (THRB)	Agonist	pIC50 8.5

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MCT1 (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OATP4A1 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)LAT1 (Substrate)OATP (Substrate)OATP1A2 (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)OATP1C1 (Substrate)OATP2B1 (Substrate)OATP3A1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acarbose	moderate
Acetohexamide	moderate
Albiglutide	moderate
Alogliptin	moderate
Aluminum hydroxide	moderate
Aminophylline	moderate
Amiodarone	moderate
Amitriptyline	moderate
Amobarbital	moderate
Amoxapine	moderate
Amphetamine	moderate
Anisindione	moderate
Apalutamide	moderate
Benzphetamine	moderate
Butabarbital	moderate
Butalbital	moderate
Calcium Phosphate	moderate
Calcium acetate	moderate
Calcium carbonate	moderate
Calcium citrate	moderate
Calcium glubionate anhydrous	moderate
Calcium gluconate	moderate
Calcium lactate	moderate
Canagliflozin	moderate
Carbamazepine	moderate
Chlorpropamide	moderate
Cholestyramine	moderate
Ciprofloxacin	moderate
Clomipramine	moderate
Colesevelam	moderate
Colestipol	moderate
Conjugated estrogens	moderate
Conjugated estrogens (topical)	moderate
Danazol	moderate
Dapagliflozin	moderate
Desipramine	moderate
Dexlansoprazole	moderate
Dextroamphetamine	moderate
Dicoumarol	moderate
Didanosine	moderate

Showing 40 of 100+.

Registered Products (23)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Levotiron	Tablet 0.025 mcg mcg	100 tab	Sun Set Drug Store	1.040
Levotiron	Tablet 0.0525 mg	100 tab	Sun Set Drug Store	1.510
Levotiron	Tablet 0.07875 mg	100 tab	Sun Set Drug Store	1.580
Euthyrox	Tablet 25 mcg	100 tab	Nabulsi Drug Store	1.950
Eltroxin Tablets	Tablet 50 mcg	100 tab	Suleiman Tannous & Sons Co. Ltd	2.050
Levotiron	Tablet 100 mcg	100 tab	Sun Set Drug Store	2.300
Levothyroxine Tablet	Tablet 50 mcg	100 tab	Burqan Drug Store	2.320
Levothyroxine Tablet	Tablet 100 mcg	100 tab	Burqan Drug Store	2.320
Euthyrox	Tablet 50 mcg	100 tab	Nabulsi Drug Store	2.990
Eltroxin Tablets	Tablet 100 mcg	100 tab	Suleiman Tannous & Sons Co. Ltd	3.480
Euthyrox	Tablet 100 mcg	100 tab	Nabulsi Drug Store	3.930
Euthyrox	Tablet 150 mcg	100 tab	Nabulsi Drug Store	5.340
TIROSINT	Capsule 75 mcg	100 cap	Kindi Drug Store	27.050
TIROSINT	Capsule 112 mcg	100 cap	Kindi Drug Store	27.050
TIROSINT	Capsule 88 mcg	100 cap	Kindi Drug Store	27.050
TIROSINT	Capsule 125 mcg	100 cap	Kindi Drug Store	27.050
TIROSINT	Capsule 200 mcg	100 cap	Kindi Drug Store	27.050
TIROSINT	Capsule 175 mcg	100 cap	Kindi Drug Store	27.050
TIROSINT	Capsule 137 mcg	100 cap	Kindi Drug Store	27.050
Tirosint	Capsule 100 mcg	100 cap	Kindi Drug Store	27.050
Tirosint	Capsule 150 mcg	100 cap	Kindi Drug Store	27.050
Tirosint	Capsule 50 mcg	100 cap	Kindi Drug Store	27.050
Tirosint	Capsule 25 mcg	100 cap	Kindi Drug Store	27.050