Active ingredients: Thyrotropin alfa
THYROGEN 0.9 mg powder for solution for injection
Why is Thyrogen used? What is it for?
Mitoxantrone belongs to a group of drugs known as antineoplastics or anticancer drugs. It also belongs to a subgroup of drugs called anthracycline derivatives. Mitoxantrone works by interfering with the growth of cancer cells and killing them progressively and is used to treat the following diseases:
- Advanced (metastatic) breast cancer.
- Non-Hodgkin's lymphomas, i.e. tumors of the lymphatic system.
- Acute non-lymphocytic leukemia in adults. Leukemia is a type of blood cancer in which the bone marrow produces too much white blood cells.
For the treatment of the above forms of cancer, Mitoxantrone Sandoz can be used alone or together with other anticancer medicines.
- Advanced prostate cancer pain when:
- Prostate cancer has not responded adequately to hormone treatment (it is refractory to therapy).
- The pain reliever treatment used is not effective or adequate pain medications cannot be taken.
In these circumstances Mitoxantrone Sandoz is administered together with low dose cortisone drugs (e.g. prednisone).
Contraindications When Thyrogen is not to be used
Do not take Mitoxantrone Sandoz:
- If you are allergic (hypersensitive) to mitoxantrone.
- If you are allergic (hypersensitive) to any of the other ingredients of Mitoxantrone Sandoz (Further information).
- If you suffer from myelosuppression (the bone marrow does not produce enough red blood cells).
- If you are breastfeeding (Pregnancy and breastfeeding).
- By injection into the spinal fluid (intrathecal administration).
- By injection into the artery (intra-arterial administration).
Precautions for use What you need to know before taking Thyrogen
Take special care with Mitoxantrone Sandoz:
- If your bone marrow is not functioning properly (you are depressed) or if your general health is not good:
- Your doctor will do more frequent blood tests, especially to check the number of white blood cells (neutrophils).
- If you have already had:
- A chest radiotherapy treatment.
- A heart disease.
In these cases, the likelihood of developing more serious heart problems increases, such as:
- Heart failure or decreased heart function.
If you have such heart problems:
- You should still take the total dose of Mitoxantrone Sandoz.
- You must have regular checks to check the functioning of the heart.
- If you have contracted infections: these must be treated before or at the time of treatment with Mitoxantrone Sandoz.
- Note that Mitoxantrone Sandoz can cause abnormal staining of:
- Urine (which may take on a blue-green color for up to a day after treatment).
- Skin and nails (which can turn blue).
- Whites of the eyes (which may take on a blue color).
In all these cases the coloring is temporary and can last a few days.
Interactions Which drugs or foods may change the effect of Thyrogen
Tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.
Also take special care if you are taking any of the following medicines:
- Other drugs that decrease the activity of the bone marrow (myelosuppressive drugs eg other anticancer agents) which, when taken together with Mitoxantrone Sandoz, can be more harmful to the marrow and can aggravate the damage to it caused by Mitoxantrone Sandoz.
- Other medicines potentially harmful to the heart (eg anthracycline drugs), as the negative effect produced by these medicines may increase.
- Topoisomerase II inhibitors (a group of anticancer drugs including mitoxantrone) in combination with other antineoplastic agents and / or radiotherapy. They can cause:
- A cancer of the white blood cells (acute myeloid leukemia - AML).
- A bone marrow disease that causes abnormal blood cell formation and leads to the development of leukemia (myelodysplastic syndrome - MDS).
- Vaccines. Vaccines may not work during treatment with Mitoxantrone Sandoz.
Warnings It is important to know that:
Pregnancy and breastfeeding
Ask your doctor for advice before taking any medicine.
Mitoxantrone Sandoz can cause fetal harm, so you should not take Mitoxantrone if:
- are pregnant (especially in the first trimester of pregnancy)
- think you are pregnant or trying to conceive a child.
If you become pregnant while taking Mitoxantrone Sandoz, you must inform your doctor and stop treatment immediately. She must avoid getting pregnant. If you or your partner are being treated with Mitoxantrone Sandoz, effective contraception should be used both during therapy and for at least 6 months after stopping treatment.
Mitoxantrone Sandoz must not be taken while breastfeeding. You must stop breastfeeding before starting therapy with Mitoxantrone Sandoz as mitoxantrone can be absorbed by the baby through breast milk.
Driving and using machines
Mitoxantrone Sandoz may have a mild or moderate effect on the ability to drive or use machines as a result of possible side effects of the treatment (see section 4 "Possible side effects").
Do not drive or use any tools or machines if you experience symptoms.
Important information about some of the ingredients of Mitoxantrone Sandoz
This medicinal product contains 0.148 mmol / ml sodium.
1 vial of 5 ml of solution contains 0.739 mmol of sodium.
1 vial of 10 ml of solution contains 1.478 mmol of sodium.
This should be taken into account by patients on a controlled sodium diet.
Dosage and method of use How to use Thyrogen: Dosage
Mitoxantrone Sandoz will be given to you by a doctor or nurse. The drug must always be administered by intravenous infusion (into a vein) and must always be diluted before use. During the infusion the drug may escape from the vein (extravasation) and in this case the infusion must be stopped immediately and taken up in another blood vessel You must avoid contact of Mitoxantrone Sandoz especially with the skin, mucous membranes and eyes.
The doctor will calculate the dose of Mitoxantrone Sandoz suitable for your case which will be obtained in relation to the extension of your body surface expressed in square meters. During the therapy you will also undergo regular blood tests on the basis of which the "adjusting the dosage of the medicine.
Children and adolescents
There is limited experience with the use of Mitoxantrone Sandoz in children and adolescents.
The usual dose of Mitoxantrone Sandoz is:
Metastatic breast cancer, Non-Hodgkin's lymphomas When mitoxantrone is used alone (alone):
- The first dose corresponds to 14 mg per square meter of body surface, administered as a single intravenous dose. Administration can be repeated after 21 days if blood values have returned to acceptable levels.
If your bone marrow reserve is low, the first dose of treatment should be lower (i.e. 12 mg per square meter) than usual.
The doctor will then establish the exact subsequent doses to be taken which will depend on the extent and duration of the decrease (myelosuppression) in the activity of the bone marrow.
In the case of use in combination therapy (for example with other cytotoxic agents such as cyclophosphamide and 5-fluorouracil or methotrexate and mitomycin C):
- In general, you will be given between 2 and 4 mg less per square meter than when Mitoxantrone Sandoz is used alone.
Acute non-lymphocytic leukemia
When Mitoxantrone Sandoz is used on its own to treat relapse (i.e. when the cancer has come back):
- the recommended dosage is 12 mg per square meter, administered as a single daily intravenous dose, for five days (corresponding to a total dose of 60 mg / m2 over five days).
When Mitoxantrone Sandoz is used in combination with other anticancer medicines (e.g. cytarabine, etoposide):
- your doctor will work out the exact dose of each medicine you will need to take.Your dosage may need to be adjusted if:
- The combination of drugs causes bone marrow depression greater than that produced by therapy with Mitoxantrone Sandoz alone.
- You have liver or kidney disease.
Treatment of pain from hormone-refractory prostate cancer
The recommended dose is 12 mg per square meter administered as follows:
- short-term intravenous infusion
- at intervals of 21 days
- in combination with oral prednisone 10 mg (a cortisone drug that helps depress the immune system).
Your doctor will decide on any dose adjustments that will depend on the extent and duration of the decrease (myelosuppression) in bone marrow activity.
Overdose What to do if you have taken too much Thyrogen
The liver, kidneys, digestive system and its ability to produce blood cells can be damaged. In rare cases, severe leukopenia (an abnormal drop in the number of white blood cells) with infection has resulted in death. Your doctor will closely monitor your health and treat any of these symptoms that may arise.
If you have any questions about the use of this medicine, ask your doctor.
Side Effects What are the side effects of Thyrogen
Like all medicines, Mitoxantrone Sandoz can cause side effects, although not everybody gets them.
The following frequencies were used to assess undesirable effects:
Very common:
- Myelosuppression (decrease in the activity of the bone marrow) which limits the amount of Mitoxantrone Sandoz that can be administered. The bone marrow may experience major and more prolonged depression if:
- you have had chemotherapy or radiotherapy.
- Bone marrow hypoplasia (abnormal decrease in the number of blood cells in an organ or tissue).
- Transient leukopenia: low number of leukocytes (white blood cells), with the lowest value reached between 10 and 13 days after treatment. In 6% of cases, leukopenia is severe.
- Anemia (when the number of red blood cells in the body is insufficient).
- Decrease in the number of a particular species of white blood cells (granulocytopenia and neutropenia).
- Abnormal amount of white blood cells (leukocytes).
- Nausea and (mild) vomiting occur in about half of patients. Only in 1% of subjects nausea and vomiting manifest in severe form.
- Stomatitis (inflammation of the mucous membrane of the mouth).
- Diarrhea.
- Abdominal pain.
- Constipation.
- Mucositis (inflammation of the mucous membranes).
- Alteration of taste.
- Alopecia (hair loss). Hair loss occurs in about half of patients. Alopecia rarely occurs in severe form.
- Transient changes in the electrocardiogram (ECG) after long-term treatment.
- Arrhythmia (irregular heartbeat).
- Increased concentration of urea in the blood.
- Infections. - Upper respiratory tract infections.
- Urinary tract infections.
- Blood loss (haemorrhage).
- Fever.
- Amenorrhea (absence of menstruation).
Common:
- Dizziness
- Drowsiness.
- Neuritis (inflammation of the nerves).
- Convulsions (seizures).
- Mild paraesthesia (tingling).
- Headache.
- The amount of blood that can be pumped from the left chamber of the heart is reduced, but there are no symptoms.
- Rhinitis (itchy and runny nose).
- Change in the color of the urine. This happens within 24 hours of taking Mitoxantrone Sandoz.
- Kidney disorders (nephrotoxicity).
- Increased levels of liver enzymes (in blood tests).
- Changes in blood test results (increase in serum creatinine level and serum nitrogen).
- Thrombocytopenia (low platelet count - a type of cell involved in blood clotting).
- Heart failure after long-term treatment, sinus bradycardia (reduced heart rate).
- Heart problems which can cause shortness of breath or swelling of the ankles
- Chest pain
- Gastrointestinal bleeding (in the stomach or intestines).
- Rash.
- Erythema (inflammation of the skin).
- Anorexia (loss of appetite).
- Pneumonia (inflammation of the lungs).
- Sepsis (blood poisoning).
- Hypotension (lowering of blood pressure).
- Fatigue.
- Edema (swelling).
- Hepatotoxicity (liver changes).
Uncommon:
- Dyspnea (shortness of breath).
- Blue coloring of the skin and nails.
- Reversible blue coloring of the whites of the eyes.
- Allergic reactions including rash (rash or redness), wheezing (shortness of breath) and hypotension (low blood pressure).
- Anxiety.
- Confusion.
Rare:
- Tumor lysis syndrome. This syndrome causes hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia (high uric acid, potassium and phosphate levels and low calcium levels in the blood) and has occurred when Mitoxantrone Sandoz was used in combination with other medicines. It also occurred when Mitoxantrone Sandoz was given alone.
Very rare:
- Change in body weight.
Frequency not known:
- Acute leukemia (a type of white blood cell cancer).
- Acute myeloid leukemia (AML - a type of white blood cell cancer).
- Myelodysplastic syndrome (MDS - a bone marrow disease that causes abnormal blood cell formation leading to leukemia). AML and MDS can be caused by topoisomerase II inhibitors when used concomitantly with other anticancer drugs and / or radiotherapy. Topoisomerase II inhibitors are a group of anticancer drugs including mitoxantrone.
- Conjunctivitis (inflammation of the membrane covering the eye and eyelids).
- Cardiomyopathy (weakening or alteration of the structure of the heart muscle).
- Myocardial infarction (heart attack).
- Inflammation of the pancreas (pancreatitis).
- Opportunistic infections (infections caused by microorganisms that usually do not cause disease in a healthy immune system).
- Hyperuricaemia (increased levels of uric acid in the blood).
- Extravasation (leakage of the drug from the blood vessel onto the tissue surrounding the injection site) which can cause:
- Erythema (redness).
- Swelling.
- Ache.
- Burning and / or blue discoloration of the skin.
- Tissue necrosis (cell death of a tissue) resulting in the need for debridement (process of removing dead cells) and skin grafts (skin transplant).
- Phlebitis (local inflammation of a vein).
- Hematomas.
- Weakness.
- Anaphylactic reaction including anaphylactic shock (allergic reaction causing difficulty in breathing or swelling of the face, lips or tongue).
- Nail alterations (eg detachment of the nail from its bed, change in the texture and structure of the nails).
If you have leukemia you may experience more frequent and serious side effects and in particular stomatitis (inflammation of the inside of the mouth) and mucositis (inflammation of the mucous membranes).
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor.
Expiry and Retention
Keep Mitoxantrone Sandoz out of the reach and sight of children.
Do not use Mitoxantrone Sandoz after the expiry date which is stated on the label. The expiry date refers to the last day of the month.
Do not dispose of the medicine via wastewater or household waste: this will help protect the environment.
Other Information
What Mitoxatrone Sandoz contains
The active ingredient is mitoxantrone (as hydrochloride).
Each ml of Mitoxantrone Sandoz contains 2 mg of mitoxantrone (as hydrochloride).
The other excipients are:
- sodium chloride
- sodium acetate
- glacial acetic acid
- sodium sulfate
- hydrochloric acid (for pH adjustment)
- water for injections
What Mitoxantrone Sandoz 2 mg / ml, concentrate for solution for infusion looks like and contents of the pack
Mitoxantrone Sandoz 2 mg / ml concentrate for solution for infusion is a clear, blue, particle-free solution supplied in clear glass vials inside a carton.
1, 5 or 10 identical vials, containing 10 mg of mitoxantrone in 5 ml or 20 mg of mitoxantrone in 10 ml, are packaged in cardboard boxes.
Vials containing 5ml or 10ml of mitoxantrone are available.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
THYROGEN 0.9 MG POWDER FOR SOLUTION FOR INJECTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial of Thyrogen contains a nominal value of 0.9 mg of thyrotropin alfa.
After reconstitution, each vial of Thyrogen contains 0.9 mg of thyrotropin alfa in 1.0 ml.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Powder for solution for injection. White or off-white lyophilized powder.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Thyrogen is indicated in serum thyroglobulin (Tg) testing with or without radioactive iodine imaging to detect thyroid residues and well-differentiated thyroid carcinoma in patients receiving hormone suppressive therapy (THST) following thyroidectomy.
Patients with well-differentiated low-risk thyroid carcinoma, who have undetectable levels of serum Tg during THST and no increase in Tg levels following stimulation with TSH rh (recombinant human), may be followed up by measuring the levels of Tg stimulated by rh TSH.
Thyrogen is indicated for pre-therapeutic stimulation in combination with radioactive iodine from 30 mCi (1.1 GBq) to 100 mCi (3.7 GBq) for the ablation of residual thyroid tissue, in patients undergoing sub-total thyroidectomy or total in the presence of well-differentiated thyroid cancer, not showing distant metastatic thyroid cancer (see section 4.4).
04.2 Posology and method of administration
Therapy should be supervised by physicians experienced in the treatment of thyroid cancer.
Dosage
The recommended posology is two 0.9 mg doses of thyrotropin alfa, to be administered by intramuscular injection only with an interval of 24 hours.
Pediatric population
Due to insufficient data available on the use of the medicinal product in pediatric patients, Thyrogen should only be given to children in exceptional cases.
Senior citizens
The results of the controlled studies show no differences in the safety and efficacy of Thyrogen between adult patients under the age of 65 and over the age of 65 when Thyrogen is used for diagnostic purposes.
No dose adjustment is necessary in the elderly (see section 4.4).
Patients with renal / hepatic insufficiency
Data from post-marketing surveillance and published information suggest that elimination of Thyrogen is significantly slower in dialysis-dependent patients with end stage renal disease (ESRD), resulting in prolonged elevation of blood levels. thyrotropic hormone (TSH) for several days after treatment. This may increase the risk of headache and nausea. patients.
In patients with significant renal insufficiency, radioactive iodine activity should be carefully determined by the nuclear medicine specialist.
Administration of Thyrogen to patients with impaired liver function does not require special considerations.
Method of administration
After reconstitution with water for injections, 1.0 ml of solution (0.9 mg thyrotropin alfa) is administered by intramuscular injection into the buttock. For instructions on reconstitution of the medicinal product before administration, see section 6.6.
For radioactive iodine diagnostic investigations or ablation, radioactive iodine administration should occur 24 hours after the final Thyrogen injection. The diagnostic scan must be performed between 48 and 72 hours after the administration of the radioactive iodine, while the post-ablation scintigraphy can be postponed for a few days, to allow the decrease of the background activity.
For the follow-up diagnostic analysis of serum thyroglobulin (Tg), the serum sample should be collected 72 hours after the final Thyrogen injection.
The use of Thyrogen in the thyroglobulin (Tg) test for the follow-up of patients with well-differentiated thyroid cancer following thyroidectomy should be in accordance with official guidelines.
04.3 Contraindications
• Hypersensitivity to bovine or human thyrotropic hormone or to any of the excipients listed in section 6.1.
• Pregnancy (see section 4.6)
04.4 Special warnings and appropriate precautions for use
Thyrogen Not it must be administered intravenously.
If used as an alternative to the suspension of thyroid hormones, the combination of Total Body Scintigraphy (WBS) and the Thyroglobulin test (Tg test) after the administration of Thyrogen ensures maximum sensitivity in detecting thyroid residues or thyroid carcinoma. False negatives can be obtained with Thyrogen. In case of strong suspicion on the presence of metastatic lesions, it is good to consider as confirmation the possibility of a total body scan (WBS) after suspension of hormone replacement therapy and a Thyroglobulin test.
The presence of antibodies to Tg (TgAb) is to be expected in 18-40% of patients with differentiated thyroid cancer and can cause false negatives in serum Tg measurements. Therefore, it is necessary to proceed with the dosage of both TgAb and Tg.
A careful benefit / risk assessment should be made when administering Thyrogen to elderly high-risk patients with heart disease (eg valvulopathy, cardiomyopathy, coronary artery disease, as well as previous or current tachyarrhythmia, including atrial fibrillation), who have not undergone thyroidectomy.
Thyrogen is known to cause transient but significant elevation in serum thyroid hormone concentrations when administered to patients with substantial thyroid tissue still in place. A careful individual risk-benefit assessment is therefore necessary in patients who show significant residues of thyroid tissue.
Long-term data on the use of the lower dose of radioactive iodine are not yet available.
Effect on tumor growth and / or size:
In patients with thyroid cancer, several cases of tumor growth stimulation reported during withdrawal of thyroid hormones for diagnostic procedures have been attributed to an associated prolonged increase in TSH levels.
There is a theoretical possibility that Thyrogen, like thyroid hormone withdrawal, may stimulate tumor growth. In clinical trials with thyrotropin alfa, which results in a short-term increase in serum TSH levels, no cases of tumor growth have been established. .
Following the increase in TSH levels after Thyrogen administration, patients with metastatic thyroid cancer, particularly in confined sites such as brain, spinal cord and orbit or with infiltration of the neck, may present with local edema or focal hemorrhage at the site. metastases resulting in an increase in tumor size. This may lead to acute symptoms depending on the anatomical location of the tissue. For example, hemiplegia, hemiparesis and vision loss have occurred in patients with central nervous system metastases. Laryngeal edema, respiratory distress requiring tracheostomy and pain at the site of metastasis have also been reported. Pre-treatment with corticosteroids is recommended for patients in whom local tumor expansion may compromise vital anatomical structures.
Sodium
This medicine contains less than 1 mmol (23 mg) sodium per injection, ie it is essentially 'sodium-free'.
04.5 Interactions with other medicinal products and other forms of interaction
No formal interaction studies of Thyrogen with other medicinal products have been performed
In clinical studies, no interactions were observed between Thyrogen and the thyroid hormones triiodothyronine
(T3) and thyroxine (T4), when given simultaneously.
The use of Thyrogen allows radioactive iodine imaging while patients are in the euthyroid state, during thyroid hormone suppression treatment. Radioactive iodine kinetics data indicate that, compared to the hypothyroid state with decreased renal function, clearance of radioactive iodine is approximately 50% greater under euthyroid conditions, resulting in less retention of radioactive iodine in the body during imaging. This factor must be taken into consideration when selecting radioactive iodine activity for " imaging.
04.6 Pregnancy and breastfeeding
Pregnancy
Animal reproduction studies have not been performed with Thyrogen.
It is not known whether Thyrogen can cause fetal harm when administered to a pregnant woman, or whether it can interfere with reproductive capacity.
The combination of Thyrogen and total body scan for diagnostic purposes with radioactive iodine is contraindicated during pregnancy (see section 4.3), due to the resulting exposure of the fetus to a high dose of radioactive substances.
Feeding time
It is unknown whether thyrotropin alfa and / or its metabolites are excreted in human milk. A risk to the infant cannot be excluded. Thyrogen should not be used while breastfeeding.
Fertility
It is not known whether Thyrogen can affect the fertility of humans.
04.7 Effects on ability to drive and use machines
Thyrogen may reduce the ability to drive and use machines as dizziness and headache have been reported.
04.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions are nausea and headache, occurring in approximately 11% and 6% of patients, respectively.
Table of adverse reactions
The adverse reactions included in the table are a combination of the adverse reactions from six prospective clinical trials (N = 481) and the undesirable effects that were reported to Genzyme following registration of Thyrogen.
Within each frequency class, adverse reactions are listed in order of decreasing severity. Frequencies are classified as very common (≥1 / 10), common (≥1 / 100,
Description of selected adverse reactions
In patients whose thyroid gland is partially or completely present, very rare cases of hyperthyroidism or atrial fibrillation have been observed following administration of Thyrogen 0.9 mg.
Rare manifestations of hypersensitivity have been reported both clinically and post-marketing: urticaria, rash, itching, flushing, and respiratory signs and symptoms.
In clinical studies of 481 patients, no patient developed antibodies to thyrotropin alfa after single or limited repeated dosing (27 patients) of the product. It is not recommended to perform the TSH assay after administration of Thyrogen. It cannot be excluded. the formation of antibodies that could interfere with the assays for endogenous TSH performed as part of the normal follow-up.
After treatment with Thyrogen there is a possibility of enlargement of residual thyroid tissue, or of metastases. This can lead to acute symptoms that depend on the anatomical location of the tissue. For example, hemiplegia, hemiparesis or loss of vision have occurred in patients with CNS metastases. Laryngeal edema, respiratory distress requiring tracheostomy and pain at the site of metastasis have also been reported following administration of Thyrogen. For patients in whom local tumor expansion may compromise vital anatomical structures it is recommended that pre-treatment with
corticosteroids.
Very rare cases of stroke in female patients have been reported from worldwide post-marketing experience. The relationship to Thyrogen administration is unknown.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
04.9 Overdose
Data on exposure to doses beyond the recommended dose are limited to clinical trials and a special therapy program only. Three patients included in clinical trials and one part of the special therapy program experienced symptoms after receiving higher than recommended doses of Thyrogen. Two Patients experienced nausea after an im dose of 2.7 mg and in one of them nausea was accompanied by weakness, dizziness and headache. The third patient reported nausea, vomiting and flushing after an im dose of 3.6 mg. "As part of the special treatment program, a 77-year-old patient with metastatic thyroid cancer and not previously subjected to thyroidectomy received 4 doses of Thyrogen 0.9 mg over 6 days, developing atrial fibrillation, heart failure and terminal myocardial infarction 2 days later.
An additional patient enrolled in a clinical trial reported symptoms after intravenous Thyrogen administration. This patient received 0.3 mg of Thyrogen as a single intravenous (IV) bolus and 15 minutes later experienced severe nausea, vomiting, diaphoresis, hypotension and tachycardia.
The recommended treatments in case of overdose are the restoration of the water balance and the administration of an antiemetic.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Hormones of the pituitary and hypothalamus and analogues, hormones of the anterior lobe of the pituitary and analogues, ATC code: H01AB01
Mechanism of action
Thyrotropin alfa (recombinant human thyrotropic hormone) is a heterodimeric glycoprotein produced by recombinant DNA technology. It is made up of two non-covalently linked subunits. The complementary DNAs encode an alpha subunit of 92 amino acid residues containing two N-bonded glycosylation sites and a beta subunit of 118 residues containing an N-bonded glycosylation site. it has biochemical properties comparable to those of endogenous human thyrotropic hormone (TSH). The binding of thyrotropin alfa to TSH receptors on thyroid epithelial cells stimulates iodine uptake and the organization, synthesis and release of thyroglobulin, triiodothyronine (T3) and thyroxine (T4).
Patients with well-differentiated thyroid cancer undergo a total or sub-total thyroidectomy. For optimal diagnosis of thyroid residues or carcinoma through radioactive iodine imaging or thyroglobulin measurement and radioactive iodine therapy of thyroid residues, a high serum TSH concentration is required to stimulate radioactive iodine intake and / or release of thyroglobulin. The common approach to achieving elevated TSH levels is to discontinue thyroid hormone suppressive therapy (THST), following which patients usually experience signs and symptoms of hypothyroidism. With the administration of Thyrogen, the TSH stimulation necessary for the uptake of radioactive iodine and the release of thyroglobulin is obtained, while patients remain in a state of euthyroidism thanks to THST, thus avoiding the morbidity associated with hypothyroidism.
Clinical efficacy and safety
Diagnostic use
The efficacy and safety of using Thyrogen in radioactive iodine imaging in combination with serum thyroglobulin assay for the diagnosis of thyroid residues and carcinoma were demonstrated in two studies. In one of the two studies, they were taken. two regimens are under consideration: 0.9 mg intramuscularly every 24 hours for two doses (0.9 mg x 2) and 0.9 mg intramuscularly every 72 hours for three doses (0.9 mg x 3). the regimens proved effective and did not statistically differ from the discontinuation of thyroid hormone administration in stimulating radioactive iodine uptake for diagnostic imaging. Compared to tests performed while patients were being treated with thyroid hormones, the two therapeutic regimens have improved sensitivity, accuracy and negative predictive value of Thyrogen-stimulated thyroglobulin, alone or in combination with radioactive iodine imaging.
In clinical trials for the detection of thyroid residues or carcinoma in patients undergoing surgery, using a thyroglobulin test with a sensitivity of 0.5 ng / mL, Thyrogen-stimulated thyroglobulin levels of 3 ng / mL , 2 ng / mL and 1 ng / mL corresponded to thyroglobulin levels measured after thyroid hormone withdrawal of 10 ng / mL, 5 ng / mL, and 2 ng / mL, respectively. Thyroglobulin with Thyrogen revealed greater sensitivity than testing thyroglobulin during THST. In particular, in a phase III study in which 164 patients participated, the dosage of thyroglobulin after administration of Thyrogen was able to detect the presence of tissue of thyroid origin from 73 to 87% of cases, while with the thyroglobulin test during THST the percentage varied from 42 to 62%, for the same cut-off values and the same reference standards.
Metastatic lesions were found in 35 patients with post-treatment examination or lymph node biopsy. Thyrogen-stimulated thyroglobulin levels exceeded 2 ng / mL in all 35 patients, whereas with thyroglobulin during THST this was the case in 79% of these patients.
Pre-therapeutic stimulation
In a controlled study of 60 evaluable patients, rates of successful ablation of thyroid residues with 100 mCi / 3.7 GBq (± 10%) of post-thyroidectomy radioactive iodine in patients with thyroid cancer were comparable for patients treated after discontinuation of thyroid hormone administration compared to treated patients after Thyrogen administration. Patients examined were adults (age> 18 years) with newly diagnosed differentiated thyroid carcinoma of the papillary or follicular, including the papillary-follicular variant, characterized mainly (54 out of 60) as T1-T2, N0-N1, M0 (TNM classification ). Success of residue ablation was assessed by radioiodine imaging and serum thyroglobulin dosing at 8 ± 1 months after treatment. All 28 patients (100%) treated after THST discontinuation and all 32 patients (100% ) treated after Thyrogen administration showed no visible uptake of radioactive iodine in the thyroid, or, if measurable, uptake
Quality of life significantly deteriorated following thyroid hormone withdrawal but remained unchanged with administration of one of the above-mentioned Thyrogen regimens for both indications.
A follow-up study was conducted on patients who had previously completed the initial study and data are available for 51 patients. The primary objective of the follow-up study was to confirm ablation status of thyroid residues by static imaging of the neck with radioactive iodine following stimulation with Thyrogen after a median follow-up of 3.7 years (range: 3 , 4 - 4.4 years) after ablation with radioactive iodine. A Thyrogen-stimulated thyroglobulin test was also performed.
Patients continued to be considered effectively ablated in the absence of scan-visible thyroid bed uptake or - if visible - uptake was less than 0.1%. For all patients considered ablated in the initial study, ablation was confirmed in the follow-up study. Furthermore, no patients had a definitive relapse in the 3.7 years of follow-up. Overall, 48/51 patients ( 94%) did not show evidence of tumor recurrence; for 1 patient there was a possible neoplastic recurrence (although it was not clear whether it was a real recurrence, or persistence of the tumor due to the regional pathology ascertained at the start of the study native to); finally, for 2 patients it was not possible to carry out an evaluation.
In summary, in the pivotal study and in the related follow-up study, Thyrogen was not inferior to the suspension of thyroid hormone as regards the elevation of TSH levels for the pre-therapeutic stimulation in association with radioactive iodine in the post-surgical ablation of the residual thyroid tissue.
Two large prospective randomized studies, the HiLo study (Mallick) and the ESTIMABL study (Schlumberger), compared methods of ablation of residual thyroid gland in patients with differentiated thyroid cancer undergoing thyroidectomy. In both studies, patients were randomized to 1 of 4 treatment groups: Thyrogen + 30 mCi 131-I, Thyrogen + 100 mCi 131-I, discontinuation of thyroid hormone + 30 mCi 131-I, or discontinuation of administration of thyroid hormone + 100 mCi 131-I and the patients were evaluated approximately 8 months later. With the HiLo study, 438 patients (tumor stages T1-T3, Nx, N0 and N1, M0) were randomized in 29 centers. As assessed by radioactive iodine imaging and Tg levels following stimulation (n = 421), ablation success rates were approximately 86% across all 4 treatment groups. All confidence intervals. 95% for the differences were within ± 10 percentage points, highlighting in particular the non-inferiority of the low dose compared to the high dose of radioactive iodine. The analysis of patients with stage T3 and N1 cancers showed that these subgroups also had a good rate of ablation efficacy as in lower-risk patient populations. In the ESTIMABL study, 752 patients with low-risk thyroid cancer (pT1 stage 1-2 cm and any stage N, or pT2 N0) were randomized (with M0 in all patients) in 24 centers. li of Tg after stimulation was 92%, with no evidence of statistically significant differences between the four groups. Considering the design of both studies, it must be taken into account that long-term data (greater than approximately 9 months) regarding the use of the lower dose of radioactive iodine is not yet available. In summary, these studies suggest that one dose low radioactive iodine in combination with thyrotropin alfa is an effective treatment (with reduced radiation exposure) and Thyrogen was not inferior to thyroid hormone withdrawal for pre-therapeutic stimulation in combination with radioactive iodine in post-surgical ablation of residual thyroid tissue.
05.2 Pharmacokinetic properties
The pharmacokinetic properties of Thyrogen were studied in patients with well-differentiated thyroid cancer who received a single injection of 0.9 mg intramuscularly. After injection, the mean peak achieved (Cmax) was 116 ± 38 mU / le occurred approximately 13 ± 8 hours after administration. The elimination half-life was 22 ± 9 hours.The major route of elimination of thyrotropin alfa is thought to be probably renal and to a lesser extent hepatic.
05.3 Preclinical safety data
Non-clinical data are limited, but reveal no special hazard for humans following the use of Thyrogen.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Mannitol
Monobasic sodium phosphate, monohydrate
Sodium dibasic, heptahydrate
Sodium chloride
06.2 Incompatibility
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products in the same injection.
06.3 Period of validity
Unopened vials
3 years.
Shelf life after reconstitution
It is recommended that the Thyrogen solution be injected within three hours.
The reconstituted medicine can be stored for 24 hours in the refrigerator at a temperature of 2 ° C - 8 ° C, protected from light, avoiding bacterial contamination.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C).
Keep the vial in the outer carton in order to protect it from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Colorless, Type I glass vials of 5 ml. The closure consists of a siliconized butyl stopper, with a sealing cap with flap. Each vial contains 1.1 mg thyrotropin alfa. After reconstitution with 1.2 ml of water for solutions for injection, withdraw 1.0 ml of solution (equivalent to 0.9 mg of Thyrogen) and administer to the patient. To have sufficient volume to allow for accurate administration, each vial of Thyrogen is formulated to contain an excess of 0.2ml.
Package contents: one or two vials per box.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
The powder for solution for injection must be reconstituted with water for injections.
Only one vial of Thyrogen is needed for each injection. Each vial of Thyrogen is for single use only.
Use an aseptic technique
Add 1.2 ml of water for injections to the Thyrogen powder contained in the vial. Gently mix the contents of the vial until the material has dissolved completely. Do not shake the solution. Once the powder is dissolved, the total volume in the vial is 1.2 ml. The pH of the Thyrogen solution is approximately 7.0. Visually inspect the Thyrogen solution in the vial to exclude foreign particles and discolouration. The Thyrogen solution must be clear and colorless. Do not use vials that have foreign particles, opacity or discolouration.
Withdraw 1.0 ml of Thyrogen solution from the vial. This amount corresponds to 0.9 mg of thyrotropin alfa to be injected.
Thyrogen does not contain preservatives. Discard any unused solution immediately.
No particular conditions for disposal.
The Thyrogen solution should be administered within three hours; however the solution will maintain its chemical stability for 24 hours, provided it is stored in a refrigerator (at a temperature between 2 ° C and 8 ° C). It is important to remember that microbiological safety depends on the aseptic conditions during the preparation of the solution.
07.0 MARKETING AUTHORIZATION HOLDER
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
Netherlands
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/99/122/001
EU / 1/99/122/002
034716011
034716023
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 9 March 2000
Date of last renewal: March 9, 2010
