TIROSINT CAPSULE

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Active ingredient:
LEVOTHYROXINE SODIUM
Available from:
IBSA INSTITUT BIOCHIMIQUE SA
ATC code:
H03AA01
INN (International Name):
LEVOTHYROXINE SODIUM
Dosage:
88MCG
Pharmaceutical form:
CAPSULE
Composition:
LEVOTHYROXINE SODIUM 88MCG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
THYROID AGENTS
Product summary:
Active ingredient group (AIG) number: 0107794006; AHFS: 68:36.04
Authorization status:
APPROVED
Authorization number:
02508524
Authorization date:
2020-11-25

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TIROCAP™ (levothyroxine sodium capsules)

Page 1 of 32

PRODUCT MONOGRAPH

INCLUDING PATIENT MEDICATION INFORMATION

Pr

TIROCAP™

Levothyroxine Sodium capsule

Capsules,13 mcg, 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg,

137 mcg, 150 mcg, 175 mcg and 200 mcg, oral

Thyroid Hormone

ATC Code: H03AA01

Institut Biochimique SA (IBSA)

Via del Piano 266

CH-6915 Pambio-Noranco,

Switzerland

Imported by:

Progress Therapeutics Inc.

14-320 Harry Walker Parkway North

Newmarket ON

Canada, L3Y 7B4

Date of Initial Authorization:

November 25, 2020

Date of Revision:

June 17, 2021

Submission Control No: 248553

TIROCAP™ (levothyroxine sodium capsules)

Page 2 of 32

TABLE OF CONTENTS

TABLE OF CONTENTS....................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ....................................................... 4

1

INDICATIONS ........................................................................................................... 4

Pediatrics .......................................................................................................... 4

Geriatrics .......................................................................................................... 4

2

CONTRAINDICATIONS ........................................................................................... 4

3

SERIOUS WARNINGS AND PRECAUTIONS BOX .............................................. 5

4

DOSAGE AND ADMINISTRATION ......................................................................... 5

Dosing Considerations..................................................................................... 5

Recommended Dose and Dosage Adjustment .............................................. 6

Administration................................................................................................... 9

Missed Dose..................................................................................................... 9

5

OVERDOSAGE ......................................................................................................... 9

6

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............ 10

7

WARNINGS AND PRECAUTIONS........................................................................ 11

Special Populations ....................................................................................... 14

7.1.1

Pregnant Women ........................................................................................ 14

7.1.2

Breast-feeding............................................................................................. 14

7.1.3

Pediatrics..................................................................................................... 14

7.1.4

Geriatrics ..................................................................................................... 15

8

ADVERSE REACTIONS......................................................................................... 16

Adverse Reaction Overview .......................................................................... 16

9

DRUG INTERACTIONS.......................................................................................... 17

Overview......................................................................................................... 17

Drug-Drug Interactions .................................................................................. 17

Drug-Food Interactions .................................................................................. 21

Drug-Laboratory Test Interactions ................................................................ 21

10

ACTION AND CLINICAL PHARMACOLOGY ...................................................... 21

10.1

Mechanism of Action .................................................................................. 21

10.2

Pharmacodynamics .................................................................................... 22

10.3

Pharmacokinetics........................................................................................ 22

11

STORAGE, STABILITY AND DISPOSAL ............................................................ 23

12

SPECIAL HANDLING INSTRUCTIONS................................................................ 23

13

PHARMACEUTICAL INFORMATION ................................................................... 24

14

CLINICAL TRIALS .................................................................................................. 24

14.1

Comparative Bioavailability Studies........................................................... 24

15

Non-Clinical Toxicology ....................................................................................... 25

TIROCAP™ (levothyroxine sodium capsules)

Page 3 of 32

16

Supporting Product Monographs ....................................................................... 25

PATIENT MEDICATION INFORMATION ......................................................................... 26

TIROCAP™ (levothyroxine sodium capsules)

Page 4 of 32

PART I: HEALTH PROFESSIONAL INFORMATION

1

INDICATIONS

TIROCAP™ (levothyroxine sodium capsules) is indicated for:

Hypothyroidism

TIROCAP™ is indicated as a replacement or supplemental therapy in adult and pediatric

patients 6 years and older for primary (thyroidal), secondary (pituitary), and tertiary

(hypothalamic) congenital or acquired hypothyroidism of any etiology in any state (including

pregnancy) except transient hypothyroidism during the recovery phase of subacute thyroiditis.

Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression

TIROCAP™ is indicated as an adjunct to surgery and radioiodine therapy in the management of

adults and pediatric patients 6 years and older with thyrotropin-dependent well-differentiated

papillary or follicular carcinoma of the thyroid.

1.1

Pediatrics

Pediatrics (>6 to <18 years of age): Based on the data submitted and reviewed by Health

Canada, the safety and efficacy of TIROCAP™ in pediatric patients has been established;

however, since it is not possible to crush the capsule and suspend it in water, Health Canada

has authorized an indication for pediatric use in patients 6 years of age and older who are able

to swallow an intact capsule (see DOSAGE AND ADMINISTRATION, Recommended Dose and

Dosage Adjustment – Pediatric Dosage).

1.2

Geriatrics

Geriatrics: TIROCAP™ is approved for use in the geriatric population. However, dosing

precautions apply (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage

Adjustment).

2

CONTRAINDICATIONS

TIROCAP™ is contraindicated in:

Patients who are hypersensitive to thyroid hormones or any ingredient in the formulation,

including any non-medicinal ingredient, or component of the container. For a complete

listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION and PACKAGING

section.

Patients with untreated subclinical thyrotoxicosis (suppressed serum TSH with normal L-

triiodothyronine/liothyronine [T

] and L-thyroxine/levothyroxine [T

] levels) or overt

thyrotoxicosis of any etiology.

Patients with acute myocardial infarction.

Patients with uncorrected/untreated adrenal insufficiency, as thyroid hormones increase

tissue demands for adrenocortical hormones and may thereby precipitate acute adrenal

crisis by increasing the metabolic clearance of glucocorticoids (see WARNINGS AND

PRECAUTIONS).

Pregnant women with hyperthyroidism treated with anti-thyroid agents. Combination

therapy of hyperthyroidism with levothyroxine and anti-thyroid agents is not indicated in

pregnancy.

TIROCAP™ (levothyroxine sodium capsules)

Page 5 of 32

3

SERIOUS WARNINGS AND PRECAUTIONS BOX

4

DOSAGE AND ADMINISTRATION

4.1

Dosing Considerations

The dosage and frequency of administration of TIROCAP™ is determined by the indication and

must be individualized in every case according to patient response and laboratory findings.

Unless bioequivalence has been established, levothyroxine sodium products from

different manufacturers should not be used interchangeably without retesting of the

patient and re-titration of the dosage, as necessary.

Hypothyroidism:

The goal of therapy for primary hypothyroidism is to achieve and maintain a clinical and

biochemical euthyroid state with consequent resolution of hypothyroid signs and symptoms. The

starting dose of levothyroxine sodium, the frequency of dose titration, and the optimal full

replacement dose must be individualized for every patient, and will be influenced by such

factors as age, weight, cardiovascular status, presence of other illness, and the severity and

duration of hypothyroid symptoms.

In patients with hypothyroidism resulting from pituitary or hypothalamic disease, the possibility of

secondary adrenal insufficiency should be considered, and if present, treated with

glucocorticoids prior to initiation of levothyroxine sodium. The adequacy of levothyroxine sodium

therapy should be assessed in these patients by measuring free T

), which should be

maintained in the upper half of the normal range, in addition to clinical assessment.

Measurement of TSH is not a reliable indicator of response to therapy for this condition.

TSH Suppression in Thyroid Cancer:

TIROCAP™ is used as ancillary therapy for the suppression of thyroid cancer following surgery

or radioactive iodine therapy. No controlled studies have compared the various degrees of TSH

suppression in the treatment of malignant thyroid nodular disease. The dose of levothyroxine

sodium

used for TSH suppression should therefore be individualized by the nature of the

disease, the patient being treated, and the desired clinical response, weighing the potential

benefits of therapy against the risks of iatrogenic thyrotoxicosis. In general, levothyroxine

sodium

should be given in the smallest dose that will achieve the desired clinical response.

Medullary and anaplastic carcinoma of the thyroid is unresponsive to TSH suppression therapy.

Pediatrics – Congenital or acquired hypothyroidism:

The levothyroxine sodium

pediatric dosage varies with age and body weight. Levothyroxine

Serious Warnings and Precautions

Thyroid hormones, including TIROCAP™, either alone or with other therapeutic agents,

should not be used for the treatment of obesity or for weight loss. In euthyroid patients, doses

within the range of daily hormonal requirements are ineffective for weight reduction. Larger

doses may produce serious or even life-threatening manifestations of toxicity, particularly

when given in association with sympathomimetic amines such as those used for their

anorectic effects.

TIROCAP™ (levothyroxine sodium capsules)

Page 6 of 32

sodium

should be given at a dose that maintains T

or FT

in the upper half of the normal range

and serum TSH in the normal range (see WARNINGS AND PRECAUTIONS, Special

Populations – Pediatrics). In general, despite the smaller body size of children, the dosage (on a

weight basis) required to sustain full development and general thriving is higher than in adults.

4.2

Recommended Dose and Dosage Adjustment

Adult Dosage

Hypothyroidism

In younger, healthy adults, therapy is usually initiated at the anticipated full replacement dose of

TIROCAP™, which is approximately 1.7 mcg/kg/day administered once daily (for example: 100-

125 mcg per day for a 70 kg adult). Dose adjustments by 13 to 25 mcg increments every 4 to 6

weeks until the patient is clinically euthyroid and the serum TSH returns to normal is required.

In older patients, the full replacement dose may be altered by decreases in T

metabolism and

levothyroxine sodium absorption. Older patients may require less than 1 mcg/kg/day.

For most patients older than 50 years and for patients under 50 years of age with a history of an

underlying cardiac disease, an initial starting dose of 25 to 50 mcg/day of TIROCAP™

recommended, with gradual increments (13 to 25 mcg) in dose at 6 to 8 week intervals, as

needed.

The recommended starting dose of TIROCAP™

in patients over 50 with cardiac disease is 13 to

25 mcg/day, with gradual dose increments (13 to 25 mcg) at 4 to 6 week intervals. If cardiac

symptoms develop or worsen, the cardiac disease should be evaluated and the dose of

TIROCAP™

reduced. Rarely, worsening angina or other signs of cardiac ischemia may prevent

achieving a TSH in the normal range.

Women who are maintained on levothyroxine sodium

during pregnancy may require increased

doses. See WARNINGS AND PRECAUTIONS, Special Populations - Pregnant Women.

Treatment of subclinical hypothyroidism may require lower than usual replacement doses e.g.,

1.0 mcg/kg/day. Patients for whom treatment is not initiated should be monitored yearly for

changes in clinical status, TSH, and thyroid antibodies.

Few patients require doses greater than 200 mcg/day. An inadequate response to daily doses

of 300 to 400 mcg/day is rare, and may suggest malabsorption, poor patient compliance, and/or

drug interactions.

Clinical and laboratory evaluations should be performed at 6 to 8 week intervals (2 to 3 weeks in

severely hypothyroid patients), and the dosage adjusted by 13 to 25 mcg increments until the

serum TSH concentration is normalized and signs and symptoms resolve. Once optimal

replacement is achieved, clinical and laboratory evaluations should be conducted at least

annually or whenever warranted by a change in patient status.

TSH Suppression in Thyroid Cancer

For well-differentiated thyroid cancer, TSH is generally suppressed to less than 0.1 mU/L and

requires doses of TIROCAP™ greater than 2 mcg/kg/day. However, in patients with high-risk

tumors, the target level for TSH suppression may be lower. Exogenous thyroid hormone may

inhibit recurrence of tumour growth and may produce regression of metastases from well-

TIROCAP™ (levothyroxine sodium capsules)

Page 7 of 32

differentiated (follicular and papillary) carcinoma of the thyroid.

TIROCAP™ should be administered with caution to patients in whom there is a suspicion of

thyroid gland autonomy, in view of the fact that the effects of exogenous hormone administration

will be additive to endogenous thyroid hormone production.

Pediatric Dosage

Congenital or Acquired Hypothyroidism

Only administer TIROCAP™ to pediatric patients 6 years and older who are able to swallow an

intact capsule.

The recommended daily dose of TIROCAP™ in pediatric patients with hypothyroidism is based

on body weight and changes with age. Therapy is usually initiated at the full replacement dose

(see Table 1).

Table 1:

Dosing Guidelines for Pediatric Hypothyroidism

Age

Daily Dose (mcg) per kg of Body Weight

a

6-12 years

4-5 mcg/kg/day

>12 years but growth and puberty incomplete

2-3 mcg/kg/day

Growth and puberty complete

1.6-1.7 mcg/kg/day

The dose should be adjusted based on clinical response and laboratory parameters (see WARNINGS

PRECA UTIONS,

Monitoring and Laboratory Tests and Special Populations – Pediatrics).

In children with severe, longstanding hypothyroidism or pre-existing cardiac insufficiency,

TIROCAP™ should be initiated gradually, with an initial 25 mcg dose for two weeks, then

increasing by 25 mcg every 2 to 4 weeks until the desired dose, based on serum T

and TSH

levels, is achieved. See WARNINGS AND PRECAUTIONS, Special Populations - Pediatrics.

Serum T

and TSH measurements should be evaluated at the following intervals, with

subsequent dosage adjustments to normalize serum total T

or FT

and TSH:

2 and 4 weeks after therapy initiation,

every 3 to 12 months thereafter until growth is completed.

Evaluation at more frequent intervals is indicated when compliance is questioned, or abnormal

laboratory values are obtained. Patient evaluation is also advisable approximately 2 to 4 weeks

after any change in dose.

Table 2 summarizes the Dosage and Administration of TIROCAP™.

TIROCAP™ (levothyroxine sodium capsules)

Page 8 of 32

Table 2:

Dosing and Administration

Medical Condition(s)

Patient

Population

Starting Dose

Dosing

Increment

Interval for Monitoring/

Dosing Increment

Therapeutic Goal

Congenital/Acquired

Hypothyroidism

Children

See Table 1

25 mcg/day

3-12 months*

level in upper

half of normal

range, normal TSH

Hypothyroidism w ith

Completed

Grow th and

Puberty

Children

1.6-1.7

mcg/kg/day

25-50

mcg/day

6-8 w eeks

Normal TSH (age-

specific reference

range)

Hypothyroidism

Adults <50

years

1.7 mcg/kg/day

25-50

mcg/day

6-8 w eeks

Normal TSH

(betw een 0.5 and

2.0 mU/L)

Adults >50

years

25-50 mcg/day

13-25

mcg/day

6-8 w eeks

Hypothyroidism w ith

Cardiac Disease

Adults <50

years

25-50 mcg/day

13-25

mcg/day

6-8 w eeks

Normal TSH

(betw een 0.5 and

2.0 mU/L)

Adults >50

years

13-25 mcg/day

13-25

mcg/day

4-6 w eeks

Severe Hypothyroidism

Adults <50

years

13-25 mcg/day

25 mcg/day

2-4 w eeks

Normal TSH

(betw een 0.5 and

2.0 mU/L)

Children

25 mcg/day

25 mcg/day

2-4 w eeks

Normal TSH (age-

specific reference

range)

Hypothyroidism (short

period) or Recently

Treated w ith

Hyperthyroidism

Adults >50

years

<1.7

mcg/kg/day

25-50

mcg/day

6-8 w eeks

Normal TSH

(betw een 0.5 and

2.0 mU/L)

Hypothyroidism w ith

Pregnancy

Pregnant

Women

1.7 mcg/kg/day

(Increased

dose may be

required)

25-50

mcg/day

Every 4 w eeks during first

half of pregnancy; at least

once betw een w eek 26

and 32; approximately 6

w eeks postpartum

Normal TSH

(trimester-specific)

and FT

in the

upper third of

normal range

1st trimester: <2.5

mU/L

2nd trimester: <3.0

mU/L

3rd trimester: <3.5

mU/L

Secondary

Hypothyroidism

Specified

level in upper

third of normal

range

Tertiary Hypothyroidism

Specified

level in upper

third of normal

range

Subclinical

Hypothyroidism

Specified

25-50 mcg/day

Adjust as

necessary

6-8 w eeks

Normal TSH

(betw een 0.5 and

2.0 mU/L)

Well-differentiated

(papillary or follicular)

Thyroid Cancers

Specified

> 2 mcg/kg/day

25-50

mcg/day

6-8 w eeks

TSH < 0.1 mU/L

TSH <0.01 mU/L

for patients w ith

high risk tumors

*For Congenital Hypothyroidism, the current guidelines recommend a 2 w eek monitoring interval at the beginning of

therapy until normalization of TSH levels

**Depending on age, duration of hypothyroidism and cardiovascular risk factor

TIROCAP™ (levothyroxine sodium capsules)

Page 9 of 32

4.3

Administration

Administer TIROCAP™ as a single daily oral dose, on an empty stomach, one-half to one hour

before breakfast.

Administer TIROCAP™ at least 4 hours before or after drugs known to interfere with

TIROCAP™ absorption (see Drug Interactions).

Evaluate the need for dose adjustments when regularly administering within one hour of certain

foods that may affect TIROCAP™ absorption (see Drug Interactions and Clinical

Pharmacology).

Swallow TIROCAP™ capsules whole, do not cut, crush, or chew.

4.4

Missed Dose

If a scheduled dose is missed, the dose should be taken as soon as the patient remembers,

unless it is almost time for the patient’s next dose. Two doses should not be taken together. If

more than two doses are missed, the patient should consult with their doctor.

5

OVERDOSAGE

Signs and Symptoms

Excessive doses of TIROCAP™ result in a hypermetabolic state indistinguishable from

thyrotoxicosis of endogenous origin. Signs and symptoms of thyrotoxicosis include

exophthalmic goiter, weight loss, increased appetite, palpitations, nervousness, diarrhea,

abdominal cramps, sweating, tachycardia, increased pulse and blood pressure, cardiac

arrhythmias, angina pectoris, tremors, insomnia, heat intolerance, fever, menstrual irregularities,

In addition, confusion and disorientation may occur. Cerebral embolism, shock, coma, and

death have been reported. Seizures have occurred in a child ingesting 18 mg of levothyroxine.

Overdose of TIROCAP™

may result in hyperthyroidism and could lead to symptoms of acute

psychosis, especially in patients at risk of psychotic disorders. Symptoms are not always

evident or may not appear until several days after ingestion of levothyroxine sodium.

Treatment of Overdosage

TIROCAP™ should be reduced in dose or temporarily discontinued if signs and symptoms of

overdosage appear.

In the treatment of acute massive levothyroxine sodium overdosage, symptomatic and

supportive therapy should be instituted immediately. Treatment is aimed at reducing

gastrointestinal absorption and counteracting central and peripheral effects, mainly those of

increased sympathetic activity. The stomach should be emptied immediately by emesis or

gastric lavage if not otherwise contraindicated (e.g., by coma, convulsions or loss of gag reflex).

Cholestyramine and activated charcoal have also been used to decrease levothyroxine sodium

absorption. Beta-receptor antagonists, particularly propranolol, are useful in counteracting many

of the effects of increased central and peripheral sympathetic activity, especially when no

contraindications exist for its use. Provide respiratory support as needed; control congestive

heart failure and arrhythmia, control fever, hypoglycemia, and fluid loss as necessary. Large

doses of antithyroid drugs (e.g., methimazole, carbimazole, or propylthiouracil) followed in one

to two hours by large doses of iodine may be given to inhibit synthesis and release of thyroid

hormones. Cardiac glycosides may be administered if congestive heart failure develops.

Glucocorticoids may be administered to inhibit the conversion of T

to T

. Plasmapheresis,

TIROCAP™ (levothyroxine sodium capsules)

Page 10 of 32

charcoal hemoperfusion and exchange transfusion have been reserved for cases in which

continued clinical deterioration occurs despite conventional therapy. Since T

is extensively

protein bound, very little drug will be removed by dialysis.

For management of a suspected drug overdose, contact your regional poison control

centre.

6

DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 3:

Dosage Forms, Strengths, Composition and Packaging.

All TIROCAP™ strengths are formulated without colour additives for patients who are sensitive

to dyes.

TIROCAP™ capsules are available in 12 different strengths and are supplied as amber-

coloured, round/biconvex capsules containing a viscous amber-coloured liquid. Capsules are

imprinted with a dosage strength specific letter on one side as follows:

Table 4:

TIROCAP™ Capsule Characteristics

Strength (mcg)

Capsule Imprint Code

Packaging Colour*

A

Light Green

E

Orange

G

White

H

Purple

J

Olive Green

K

Yellow

M

Rose

N

Brown

P

Dark Blue

S

Blue

U

Lilac

Y

Pink

*Shown on box and blister packaging, not on individual capsules.

All TIROCAP™ strengths are available in blister packages of 30 capsules (three blisters with

10 capsules each).

Route of

Administration

Dosage Form /

Strength/Composition

Non-medicinal Ingredients

Oral

Capsules

13, 25, 50, 75, 88, 100, 112,

125, 137, 150, 175 and

200 mcg

Gelatin, glycerin and water

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