Leventa (Canada)

Company: Merck Animal Health

Levothyroxine Sodium Oral Solution

FOR VETERINARY USE ONLY

DIN 02429438

Description

LEVENTA is an oral solution for dogs. Each mL contains: Active ingredients: 1 mg levothyroxine sodium (as multihydrate). Non-medicinal ingredients: Hydroxypropylbetadex, Sodium hydrogen carbonate, Sodium hydroxide and / or Hydrochloric acid. Preservatives: Ethanol.

Therapeutic Classification

Levothyroxine (L-thyroxine) sodium is therapeutically classified as a thyroid hormone.

Leventa Indications

LEVENTA is indicated for the management of hypothyroidism in dogs.

Leventa Dosage And Administration

For oral use in dogs only.

In thyroid hormone replacement therapy with L-thyroxine, the dosage and regime have to be tailored individually to each dog. A starting dosage of 20 microgram L-thyroxine sodium/kg (0.2 mL per 10 kg bodyweight) once daily is recommended. Four weeks later, dose adjustment should be performed based on the clinical response to treatment and thyroid hormone concentration evaluated 4-6 hours after administration of LEVENTA. Further assessment of thyroid hormone concentrations and dose adjustment may be repeated at 4 week intervals if required.

A maintenance dosage between 10 and 40 microgram/kg body weight once daily is generally sufficient. Depending on the dosage and on the body weight of the dog, the volume (in mL) of LEVENTA to be administered once daily can be determined using the following table:

Volume of LEVENTA (mL) to be Administered for Doses of 10, 20, 30 and 40 micrograms/kg

The dose for dogs weighing more than 50 kg should be calculated according to bodyweight in the same way.

Once a suitable dose and regime have been established, it is recommended to recheck every 6 months that thyroid hormone concentrations are appropriate.

Metabolic signs such as lethargy usually improve within two weeks after the onset of treatment whereas skin and coat changes may require 6 weeks or more of treatment before improvement is seen.

LEVENTA should be administered at the same time every day. The absorption of L-thyroxine is influenced by food (see Pharmacology) therefore LEVENTA should be administered 2-3 hours prior to feeding. If LEVENTA is to be administered with food, then the type and quantity of food should be standardized.

Instruction for Administration: Remove the child resistant cap and insert the oral dosing syringe in the plastic push-in adapter. Invert the bottle and gently draw back the syringe plunger to the desired dose. Return the bottle to the upright position and remove the syringe.

Clean the syringe by flushing with clean water and allow to dry naturally.

Contraindications

Do not use in dogs with hyperthyroidism or uncorrected adrenal insufficiency (hypoadrenocorticism). Do not use in dogs with a known hypersensitivity to levothyroxine sodium.

Leventa Cautions

LEVENTA should be used with caution in dogs with heart disease, diabetes mellitus or treated adrenal insufficiency (hypoadrenocorticism).

The clinical diagnosis of hypothyroidism should be confirmed by laboratory tests.

Use in pregnant or lactating bitches or animals intended for future breeding has not been evaluated.

Warnings

KEEP OUT OF REACH OF CHILDREN

In the case of accidental ingestion, seek medical advice immediately and show the package insert or the label to the physician. Note: LEVENTA contains a high concentration of L-thyroxine sodium and may present a risk to humans if ingested.

Wash hands after use.

In case of eye contact, flush immediately with water.

Adverse Reactions

Adverse reactions associated with treatment with L-thyroxine sodium are primarily those of hyperthyroidism possibly due to a therapeutic overdose for that individual. They include body weight loss, hyperactivity, increased heart rate, thirst, increased urination, increased appetite, vomiting and diarrhea. Rarely, skin reactions such as mild to moderate scale formation and pruritus may occur.

Although all adverse reactions are not reported, the following adverse reaction information is based on voluntary post-approval drug experience reporting. It is generally recognized that this method of reporting results in significant under-reporting of adverse drug reactions. It should be noted that suspected adverse drug reactions listed here reflect reporting and not causality. The categories of adverse reactions are listed in decreasing order of frequency by body system.

● Systemic disorders: lack of efficacy, abnormal test result, weight loss, increased appetite

● Gastro-intestinal disorders: diarrhea, emesis

● Skin and appendage disorders: alopecia, dermatitis

Information For Owners

The dosage suitable to treat your dog is decided by your veterinarian and may vary according to your dog’s needs. Please inform your veterinarian if your dog receives any other medications before or during treatment with LEVENTA.

Overdose

Clinical signs of overdose with L-thyroxine include body weight loss, hyperactivity, increased heart rate, thirst, increased urination, increased appetite and diarrhea. These signs are generally mild and fully reversible. Overdose may influence some blood parameters.

Clinical Pharmacology

L-thyroxine is identical in structure and mode of action to the thyroxine (T4) secreted physiologically and present in mammals with a normally functioning thyroid gland. Thyroxine is metabolised mainly to tri-iodothyronine (T3). T4 and T3 have a large variety of biological effects throughout the body. They are essential for the regulation of basal metabolism, cardiac function and blood flow, lipid and carbohydrate metabolism. They are also essential for the normal growth and development of the neurological and skeletal systems.

Pharmacokinetics

There is considerable variation in the pharmacokinetics between individual dogs.

Pharmacokinetic studies have shown that serum total thyroxine (TT4) concentrations after oral administration of LEVENTA at 40 µg/kg (twice the starting dose) are maximal (about 102.8 ± 32 nmol/L) at approximately 2.5 hours post dosing. The harmonic mean half-life was 14 h (range of 6.5-21.8 h). Trough concentrations were approximately 30 nmol/L. After repeated oral administration over 14 consecutive days, there was no accumulation of L-thyroxine in serum.

In a bioavailability study, dogs were given 40 µg/kg L-thyroxine orally or intravenously. The serum half-life of L-thyroxine had a harmonic mean of approximately 7 hours. Bioavailability was 22%. Concomitant administration of food with LEVENTA decreased the absorption of L-thyroxine by 55±28.7%. T_max was also significantly delayed in fed dogs (median: 5h; range 4-8 h) compared to fasted dogs (median 2.5 h; range: 1.5-5 h). L-thyroxine is highly protein bound.

In another pharmacokinetic study comparing an L-thyroxine solution and L-thyroxine tablet no significant differences were observed for any of the pharmacokinetic parameters when corrected for dose.

The major site of thyroxine (T4) metabolism is the liver. The main pathway for the metabolism of T4 is its conversion, by deiodination, to the active metabolite triiodothyronine (T3). Further deiodination of T4 and T3 leads to production of inactive compounds. Excretion is mainly observed via biliary and, to a lesser extent, urinary routes.

Drug Interactions

Some drugs, including anti-thyroid drugs, can influence thyroid function test results. Therefore the test results should be interpreted carefully in any dog receiving glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), trimethoprim-potentiated sulphonamides, antiepileptics, anaesthetics and sedatives, furosemides, and mitotane.

The following drug interactions have either been reported or may be possible in dogs receiving levothyroxine:

● Oral antacids: may reduce levothyroxine absorption; separate dose by 4 hours

● Antidiabetic Agents: levothyroxine may increase requirement for insulin or oral agents

● Corticosteroids (high dose): decreased conversion of T4 to T3

● Cardiac glycosides: In dogs with cardiac insufficiency, therapeutic response to cardiac glycosides may be decreased by L-thyroxine supplementation

● Ketamine: May cause tachycardia and hypertension

● Phenobarbital: Possible increased metabolism of thyroxine; dosage adjustment may be needed.

● Sucralfate: May reduce levothyroxine absorption; separate dose by 4 hours

Dogs treated with any of these drugs should be monitored carefully during treatment with LEVENTA.

The therapeutic response to LEVENTA may be altered by any drug that influences thyroid hormone metabolism and disposition (e.g. drugs displacing protein-binding site, modifying serum thyroxine-binding globulin concentration, or altering hepatic degradation of thyroxine or peripheral conversion of thyroxine to triiodothyronine). Thus, in case of concomitant administration of LEVENTA with a drug exhibiting one of these properties, it is recommended to recheck that thyroid hormone concentrations are appropriate and to adjust the dose of LEVENTA accordingly if needed.

Safety

As with any substitution therapy of an active endogenous hormone, it is essential that the right dose is established for each individual patient, since continuous significant overdosage will lead to hyperthyroidism and a continuous significant under dosage will not resolve the hypothyroidism. Safety was demonstrated -when LEVENTA was administered to dogs at the maximal recommended dose rate (40 µg/kg body weight) for 13 weeks. In euthyroid dogs treated at 120 and 200 µg/kg body weight once daily (3 and 5 x the maximum daily dose) for 13 weeks body weight loss, hyperactivity, transient irregular heart rhythms, soft feces, decreased cholesterol and total protein concentrations and increased glucose and inorganic phosphorus concentrations were observed. All these effects correspond to the known pharmacological effects of excessive thyroxine. These signs were reversible, with recovery occurring within 5 weeks after cessation of treatment.

Efficacy

A multicenter case series study was performed in Europe. Of the 34 dogs that were newly diagnosed with hypothyroidism and completed the dose adjustment phase, 25 were stabilized after 4 weeks, 6 after 8 weeks and a dose to control the hypothyroidism was established in all the dogs after 12 weeks of treatment. One of the 34 dogs did not complete the study. The clinical condition was improved or had resolved in 91% (30/33) of dogs after 4 weeks of treatment with LEVENTA at 20 µg/kg body weight once daily. The maintenance dose was 20 µg/kg body weight for 26/33 dogs (79%), 10 µg/kg body weight in 1/33 dogs (3%), 15 µg/kg body weight in 1/33 dogs (3%) and 30 µg/kg body weight for 5/33 dogs (15%). Once treatment with LEVENTA was initiated, rapid improvement in clinical signs was reported. Metabolic signs were the first clinical signs to resolve (within the first 4 weeks of treatment for all of them except overweight/obesity). Most of the dogs lost weight during the study (-11.3%). Dermatological signs were more persistent than metabolic ones. Signs like hyperpigmentation were still present in some cases, although less severe, at the end of the study. At the end of the study, laboratory abnormalities had resolved in more than 70% of dogs. No clinical relapse was observed during the maintenance period. Peak TT4 and thyroid stimulating hormone (TSH) concentrations were in the normal laboratory range in 24/34 dogs (71%) and in 30/34 dogs (88%), respectively, after 4 weeks of treatment with LEVENTA at 20 µg/kg body weight once daily.

A study was conducted in 10 hypothyroid dogs to evaluate the pharmacokinetic profile of oral L-thyroxine after repeated oral administration of LEVENTA at 20 µg/kg body weight once daily during a minimum of 4 consecutive weeks. On the day of pharmacokinetic evaluation, blood samples were taken pre-treatment and at T=0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24 and 34 hours post-treatment and dogs were examined for clinical signs of hypothyroidism. At T24 h, trough mean thyroxine concentrations were 23.8 ± 10.9 nmol/L with a range of 15-41 nmol/L. Peak concentrations of 55 ±11 nmol/L (C_max) were reached after approximately 5 hours (T_max). 7/10 dogs had thyroxine concentrations within the reference euthyroid range (19-46 nmol/L) for the 24 hour period of time. One dog had TT4 ≤ 2 nmol/L by 24 hours. This dog’s LEVENTA dosage was changed from 20 µg/kg once daily to 13 µg/kg twice daily. From T24h to T34h, TT4 concentrations continued to decrease, ranging from 7 to 32 nmol/L at T34h in the 9 other dogs. Thyroxine had a mean half-life of 12 hours.

The clinical evaluation conducted after the 4-week treatment period showed that the metabolic signs had resolved or improved: a mean decrease of 5.3% in body weight, at the start of the study 9/10 dogs were obese and a month later 7/10 dogs were obese. Just one of seven dogs that were apathetic at the start of treatment was apathetic 4 weeks later and only one of 6 dogs was still exercise intolerant. Improvements in the dermatological signs of hypothyroidism were also noticed.

Storage:

Refrigerate at 2 to 8°C. Store in the original container. LEVENTA can be used up to 6 months from first use.

HOW SUPPLIED

LEVENTA is available in a 30 mL bottle with a 1 mL oral dosing syringe provided.

Intervet Canada Corp., subsidiary of Merck & Co., Inc., 16750 route Transcanadienne, Kirkland, Québec H9H 4M7

1-866-683-7838

08AUG2014

^® Intervet International B.V. Used under license.

CPN: 1208276.1