Active ingredients: Clodronic acid (disodium clodronate)
CHLODRONATE ABC 100 mg / 3.3 ml solution for injection
CHLODRONATE ABC 300 mg / 10 ml solution for intravenous infusion
Why is Clodronate used - Generic drug? What is it for?
PHARMACOTHERAPEUTIC CATEGORY: Drug that acts on bone mineralization.
THERAPEUTIC INDICATIONS: Intravenous or intramuscular use. Tumor osteolysis. Multiple myeloma. Primary hyperparathyroidism. Prevention and treatment of post menopausal osteoporosis.
Contraindications When Clodronate should not be used - Generic drug
Hypersensitivity to the active substance or excipients.
Concurrent treatments with other bisphosphonates.
Precautions for use What you need to know before taking Clodronate - Generic drug
Clodronate should be used with caution in patients with renal insufficiency.
Adequate fluid intake should be maintained during treatment with clodronate. This is particularly important when clodronate is administered parenterally and in patients with hypercalcaemia or renal insufficiency.
Renal function should be monitored before and during treatment by serum creatinine, calcium and phosphate levels.
Intravenous administration of significantly higher than recommended doses can cause severe kidney damage, especially if the infusion rate is too high.
In clinical studies, asymptomatic and reversible elevations in transaminases occurred, with no changes in other liver function tests. Monitoring of transaminases is recommended (see also "Undesirable effects").
Intravenous administration should be performed by slow perfusion (2-3 hours) in 0.9% NaCl or 5% glucose solution.
Interactions Which drugs or foods can modify the effect of Clodronate - Generic drug
From a chemical point of view, the contents of the vials are incompatible with alkaline solutions or oxidizing solutions.
Concomitant use with other bisphosphonates is contraindicated.
The concomitant use of clodronate with non-steroidal anti-inflammatory drugs (NSAIDs), most often with diclofenac, has been associated with renal dysfunction.
Due to the "increased risk of" hypocalcaemia, caution should be used when co-administering clodronate with aminoglycosides.
Concomitant use of estramustine phosphate with clodronate has been reported to increase the serum concentration of estramustine phosphate up to a maximum of 80%.
Clodronate forms complexes with divalent cations which are poorly soluble in water. Therefore, clodronate should not be administered intravenously with solutions containing divalent cations (e.g. Ringer's solution).
Warnings It is important to know that:
Since the drug is eliminated predominantly by the kidney, caution is advised in the treatment of patients with renal insufficiency, particularly when the drug is administered intravenously. In such cases, the use of clodronate should be carried out only after a careful evaluation of the risk / benefit ratio and by frequently monitoring the renal function indices.
Osteonecrosis of the jaw, usually associated with tooth extraction and / or local infection (including osteomyelitis), has been reported in cancer patients receiving regimens including bisphosphonates administered primarily intravenously. Many of these patients they were also treated with chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis being treated with oral bisphosphonates.
Before starting bisphosphonate treatment in patients with concomitant risk factors (such as cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene) the need for a dental examination with appropriate preventive dental procedures should be considered.
During treatment, these patients should avoid invasive dental procedures. In patients who have developed osteonecrosis of the jaw during bisphosphonate therapy, dental surgery can exacerbate the condition.For patients requiring dental surgery, there are no data available to suggest that discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.
The clinical judgment of the physician must guide the management program of each patient, based on the individual assessment of the risk / benefit ratio.
FERTILITY, PREGNANCY AND BREASTFEEDING
FERTILITY
In animal studies, clodronate does not cause fetal harm, but large doses reduce male fertility. No clinical data on the effect of clodronate on human fertility are available. For the use of clodronate in pregnancy and lactation, see the sections "Pregnancy" and Lactation ".
PREGNANCY AND BREASTFEEDING
Although clodronate passes through the placental barrier in animals, it is not known in humans whether it passes into the fetus. Furthermore, it is not known whether clodronate can cause fetal harm or affect reproductive function in humans. a limited amount of data on the use of clodronate in pregnant women. Clodronate ABC is not recommended during pregnancy and in women of childbearing potential unprotected by effective contraceptive therapy.
In humans, it is not known whether clodronate is excreted in human milk. A risk to the suckling child cannot be excluded. Therefore, breastfeeding should be discontinued during treatment with Clodronate ABC.
ABILITY TO DRIVE VEHICLES AND ON THE USE OF MACHINERY
The drug does not alter the state of alertness, therefore it has no effect on the ability to drive and use machines
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN.
Dosage and method of use How to use Clodronate - Generic drug: Posology
Tumor osteolysis - Multiple myeloma - Primary hyperparathyroidism
The dosing schedule should be considered as a guideline and can therefore be adapted to the needs of the individual patient.
- Attack phase:
200 - 300 mg / day in a single slow intravenous administration for 3-8 days in relation to the trend of clinical and laboratory parameters (calcium, hydroxyprolinuria, etc.)
- Maintenance phase:
100 mg / day intramuscularly for 2-3 weeks.
These cycles can be repeated at variable intervals according to the evolution of the disease. The periodic evaluation of the bone resorption parameters can usefully guide the therapeutic cycles.
Prevention and treatment of post menopausal osteoporosis
Depending on the clinical picture and mineralometric values, the dosage may vary as follows:
intramuscularly 100 mg every 7 - 14 days or by intravenous infusion 200 mg every 3 - 4 weeks, for 1 year or more depending on the patient's condition.
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be reassessed in each individual patient periodically based on the potential benefits and risks, particularly after 5 or more years of use.
Clodronate is eliminated predominantly by the kidney. Therefore, adequate fluid intake should be ensured during treatment with Clodronate.
- Children
The safety and efficacy of the drug in pediatric patients have not been established.
- Senior citizens
There are no special dosage recommendations of the drug for the elderly. Clinical studies performed included patients over 65 years of age and no specific adverse events were reported for this age group.
Intravenous infusion for short-term therapy
Adequate hydration must be ensured during intravenous treatment with clodronic acid sodium salt.
- Patients with renal insufficiency It is recommended to reduce the dosage of the clodronate infusion as follows:
It is recommended to administer clodronate prior to hemodialysis and to reduce the dose by 50% on dialysis-free days, and to limit the treatment schedule to 5 days. Note that peritoneal dialysis removes clodronate poorly from the circulation.
Overdose What to do if you have taken an overdose of Clodronate - Generic Medication
Although there is no experience of overdose, it is however theoretically possible that high quantities of the product can induce hypocalcemia. In such cases, the treatment must consist in the correction of hypocalcemia by means of an adequate dietary supplement or, in severe cases, by intravenous administration of calcium. Should alterations in renal function occur due to the formation of calcium aggregates, the therapy must aim at restoring the functionality itself.
One case of uremia and liver damage has been reported following the accidental ingestion of 20,000 mg (50x400 mg) of clodronate.
- Symptoms
Increased serum creatinine and renal dysfunction have been reported with high doses of clodronate administered intravenously.
- Treatment
Treatment of overdose should be symptomatic. Adequate hydration should be ensured, and renal function and serum calcium monitored.
Side Effects What are the side effects of Clodronate - Generic drug
Intramuscular administration of clodronate may induce tenderness at the injection site, also in consideration of the duration of therapy.
In rare circumstances bisphosphonates (including clodronate) have been associated with visual and ocular disturbances. In case of such disturbances it is necessary to stop the treatment and refer to an ophthalmologist.
Osteonecrosis of the jaw, usually associated with tooth extraction and / or local infection, has been reported in patients receiving regimens including bisphosphonates administered mainly intravenously (see also Special warnings). Most of the reports concern cancer patients, but there have also been cases in patients treated for osteoporosis.
Rarely, an unusual fracture of the femur may occur particularly in patients on long-term treatment for osteoporosis. Contact your doctor if you experience pain, weakness or discomfort in the thigh, hip or groin as this may be an early indication. of a possible fracture of the femur.
The most commonly reported reaction is diarrhea, which is usually mild and is more frequent with higher dosages.
These adverse reactions can occur with both oral and intravenous treatment, although their frequency may differ.
* In patients with metastases, they may also be due to hepatic or bone involvement.
** Usually mild
The more appropriate MedDRA term is used to describe a reaction, its synonyms and related conditions.
Post-marketing experience
- Respiratory, thoracic and mediastinal disorders.
Impaired respiratory function in patients with aspirin-sensitive asthma. Hypersensitivity reactions manifesting as respiratory disturbances.
- Renal and urinary disorders
Renal insufficiency (increased serum creatinine and proteinuria), severe renal impairment especially after rapid intravenous infusion of high doses of clodronate (for dosing instructions see section 4.2 under "Intravenous infusion" chapter "Patients with renal insufficiency").
Individual cases of renal failure, rarely with fatal outcome, have been reported especially with concomitant use of NSAIDs, most often diclofenac.
- Musculoskeletal and connective tissue disorders
There have been isolated reports of osteonecrosis of the jaw, primarily in patients who had previously been treated with amino bisphosphonates such as zoledronate and pamidronate (see also section 4.4). Severe bone, joint and / or muscle pain has been reported in patients taking clodronic acid sodium salt. However, such reports have been infrequent and, in randomized placebo-controlled trials, there is no difference between patients treated with placebo or sodium salt clodronic acid. The onset of symptoms varies from days to several months after the initiation of sodium salt clodronic acid therapy.
Rarely, an unusual fracture of the femur may occur particularly in patients on long-term treatment for osteoporosis. Contact your doctor if you experience pain, weakness or discomfort in the thigh, hip or groin as this may be an early indication. of a possible fracture of the femur.
- Eye disorders
Cases of uveitis have been reported during post-marketing experience with clodronate. The following reactions have been reported with other bisphosphonates: conjunctivitis, episcleritis and scleritis. Conjunctivitis was only reported with clodronate in a patient receiving concomitant treatment with another bisphosphonate. So far, episcleritis and scleritis have not been reported with clodronate (bisphosphonate class adverse reaction).
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
It is important to notify the doctor of any undesirable effect, even if not described in the package leaflet.
Expiry and Retention
Expiry: see the expiry date printed on the package.
The expiry date refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date shown on the package
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Keep this medicine out of the reach and sight of children.
Other Information
COMPOSITION
CHLODRONATE ABC 100 mg / 3.3 ml solution for injection
Each 3.3ml vial contains
Active principle
Disodium clodronate tetrahydrate 125 mg equal to disodium clodronate 100 mg
Excipients
sodium bicarbonate, water for injections
CHLODRONATE ABC 300 mg / 10 ml solution for intravenous infusion
Each 10ml vial contains
Active principle
Disodium clodronate tetrahydrate 375 mg equal to disodium clodronate 300 mg
Excipients
sodium bicarbonate, water for injections
PHARMACEUTICAL FORM AND CONTENT
Solution for injection, 6-12 ampoules of 100 mg / 3.3 ml
Solution for intravenous infusion, 6 ampoules of 300 mg / 10 ml.
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
CHLODRONATE ABC - SOLUTION FOR INJECTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
CHLODRONATE ABC 100 mg / 3.3 ml solution for injection
Each vial contains:
Active principle: disodium clodronate tetrahydrate 125 mg equal to disodium clodronate 100 mg.
CHLODRONATE ABC 300 mg / 10 ml solution for intravenous infusion
Each vial contains:
Active principle: disodium clodronate tetrahydrate 375 mg equal to disodium clodronate 300 mg.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Injectable solution.
Solution for intravenous infusion.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Intravenous or intramuscular use:
• Tumor osteolysis.
• Multiple myeloma.
• Primary hyperparathyroidism.
• Prevention and treatment of post menopausal osteoporosis.
04.2 Posology and method of administration
Tumor osteolysis - Multiple myeloma - Primary hyperparathyroidism
The dosing schedule should be considered as a guideline and can therefore be adapted to the needs of the individual patient.
a) Attack phase: 200 - 300 mg / day in a single slow intravenous administration for 3-8 days in relation to the progress of clinical and laboratory parameters (calcemia, hydroxyprolinuria, etc.)
b) Maintenance phase: 100 mg / day intramuscularly for 2-3 weeks.
These cycles can be repeated at variable intervals according to the evolution of the disease. The periodic evaluation of the bone resorption parameters can usefully guide the therapeutic cycles.
Prevention and treatment of post menopausal osteoporosis
Depending on the clinical picture and mineralometric values, the dosage may vary, as follows:
Intramuscularly 100 mg every 7-14 days or by intravenous infusion 200 mg every 3-4 weeks, for 1 year or more depending on the patient's condition.
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be reassessed in each individual patient periodically based on the potential benefits and risks, particularly after 5 or more years of use.
Clodronate is eliminated predominantly by the kidney. Therefore, adequate fluid intake should be ensured during treatment with Clodronate.
Children
The safety and efficacy of the drug in pediatric patients have not been established.
Senior citizens
There are no special dosage recommendations of the drug for the elderly. Clinical studies performed included patients over 65 years of age and no specific adverse events were reported for this age group.
Patients with renal insufficiency
It is recommended to reduce the dosage of the clodronate infusion as follows:
It is recommended to administer before hemodialysis, and to reduce the dose by 50% on dialysis-free days, and to limit the treatment schedule to 5 days. Note that peritoneal dialysis removes clodronate poorly from the circulation.
04.3 Contraindications
Hypersensitivity to the active substance or excipients.
Concurrent treatments with other bisphosphonates.
04.4 Special warnings and appropriate precautions for use
Adequate fluid intake should be maintained during treatment with clodronate. This is particularly important when clodronate is administered intravenously and in patients with hypercalcaemia or renal insufficiency.
Renal function should be monitored before and during treatment by serum creatinine, calcium and phosphate levels.
In clinical studies, asymptomatic and reversible elevations in transaminases occurred, with no changes in other liver function tests. Monitoring of transaminases is recommended (see also section 4.8).
Clodronate should be used with caution in patients with renal insufficiency (see dosage adjustments under "Dosage and method of administration").
Intravenous administration of significantly higher than recommended doses can cause severe kidney damage, especially if the infusion rate is too high.
Since the drug is eliminated predominantly by the kidney, caution is advised in the treatment of patients with renal insufficiency, particularly when the drug is administered intravenously. In such cases, the use of clodronate should be carried out only after a careful evaluation of the risk / benefit ratio and by frequently monitoring the renal function indices.
In the initial phase of oncological treatment and in any case in the most serious forms, it is advisable to administer the product in 0.9% NaCl or in 5% glucose solution, intravenously, by slow perfusion (2-3 hours).
Osteonecrosis of the jaw, usually associated with tooth extraction and / or local infection (including osteomyelitis), has been reported in cancer patients receiving regimens including intravenous bisphosphonates. Many of these patients were also treated with chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis being treated with oral bisphosphonates.
Before starting bisphosphonate treatment in patients with concomitant risk factors (such as cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene) the need for a dental examination with appropriate preventive dental procedures should be considered.
During treatment, these patients should avoid invasive dental procedures. In patients who have developed osteonecrosis of the jaw during bisphosphonate therapy, dental surgery can exacerbate the condition. For patients requiring dental surgery, there are no data available to suggest that discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.
The clinical judgment of the physician must guide the management program of each patient, based on the individual assessment of the risk / benefit ratio.
Atypical fractures of the femur
Atypical subtrochanteric and shaft fractures of the femur have been reported, mainly in patients on long-term bisphosphonate therapy for osteoporosis. These short transverse or oblique fractures can occur anywhere in the femur from just below the lesser trochanter to above the supracondylar line. These fractures occur spontaneously or after minimal trauma and some patients experience thigh or groin pain, often associated with imaging findings and radiographic evidence of stress fractures, weeks or months before the onset of stress fractures. a complete femoral fracture. Fractures are often bilateral; therefore in bisphosphonate-treated patients who have sustained a femoral shaft fracture, the contralateral femur should be examined. Limited healing of these fractures has also been reported. In patients with suspected atypical femoral fracture, consideration should be given to discontinuing bisphosphonate therapy pending an assessment of the patient based on the individual benefit-risk ratio.
During treatment with bisphosphonates, patients should be advised to report any pain in the thigh, hip or groin and any patient who exhibits such symptoms should be evaluated for the presence of an incomplete fracture of the femur.
04.5 Interactions with other medicinal products and other forms of interaction
From a chemical point of view, the contents of the vials are incompatible with alkaline solutions or oxidizing solutions.
Concomitant use with other bisphosphonates is contraindicated.
The concomitant use of clodronate with non-steroidal anti-inflammatory drugs (NSAIDs), most often with diclofenac, has been associated with renal dysfunction.
Due to the "increased risk of" hypocalcaemia, caution should be used when co-administering clodronate with aminoglycosides.
Concomitant use of estramustine phosphate with clodronate has been reported to increase the serum concentration of estramustine phosphate up to a maximum of 80%.
Clodronate forms complexes with divalent cations which are poorly soluble in water. Therefore, clodronate should not be administered intravenously with solutions containing divalent cations (e.g. Ringer's solution).
04.6 Pregnancy and breastfeeding
Fertility
In animal studies, clodronate does not cause fetal harm, but large doses reduce male fertility.
No clinical data on the effect of clodronate on human fertility are available.
Pregnancy
Although clodronate passes through the placental barrier in animals, it is not known in humans whether it passes into the fetus. Furthermore, it is not known whether clodronate can cause fetal harm or affect reproductive function in humans. a limited amount of data on the use of clodronate in pregnant women. CHLODRONATE ABC is not recommended during pregnancy and in women of childbearing potential unprotected by effective contraceptive therapy.
Feeding time
In humans, it is not known whether clodronate is excreted in human milk. A risk to the suckling child cannot be excluded. Therefore, breastfeeding should be discontinued during treatment with CHLODRONATE ABC.
04.7 Effects on ability to drive and use machines
The drug does not alter the state of alertness, therefore it has no effect on the ability to drive and use machines
04.8 Undesirable effects
Intramuscular administration of clodronate may induce tenderness at the injection site, also in consideration of the duration of therapy.
In rare circumstances bisphosphonates (including clodronate) have been associated with visual and ocular disturbances. In case of such disturbances it is necessary to stop the treatment and refer to an ophthalmologist.
Osteonecrosis of the mandible and / or maxilla, generally associated with tooth extraction and / or local infection, has been reported in patients receiving regimens including bisphosphonates administered mainly intravenously (see also section 4.4). Most of the reports concern cancer patients, but there have also been cases in patients treated for osteoporosis.
The most commonly reported reaction is diarrhea, which is usually mild and is more frequent with higher dosages.
These adverse reactions can occur with both oral and intravenous treatment, although their frequency may differ.
Post-marketing experience
Respiratory, thoracic and mediastinal disorders
Impaired respiratory function in patients with aspirin-sensitive asthma. Hypersensitivity reactions manifesting as respiratory disturbances.
Renal and urinary disorders
Renal insufficiency (increased serum creatinine and proteinuria), severe renal impairment especially after rapid intravenous infusion of high doses of clodronate (for dosing instructions see section 4.2 under "Intravenous infusion" chapter "Patients with renal insufficiency").
Individual cases of renal failure, rarely with fatal outcome, have been reported especially with concomitant use of NSAIDs, most often diclofenac.
Musculoskeletal and connective tissue disorders
There have been isolated reports of osteonecrosis of the jaw, primarily in patients who had previously been treated with amino bisphosphonates such as zoledronate and pamidronate (see also section 4.4). Severe bone, joint and / or muscle pain has been reported in patients taking clodronic acid sodium salt. However, such reports have been infrequent and, in randomized placebo-controlled trials, there is no difference between patients treated with placebo or sodium salt clodronic acid. The onset of symptoms varies from days to several months after the initiation of sodium salt clodronic acid therapy.
The following reactions have been reported during post-marketing experience (frequency rare): Atypical subtrochanteric and diaphyseal fractures of the femur (bisphosphonate class adverse reaction).
04.9 Overdose
Although there is no experience of overdose, it is however theoretically possible that high quantities of the product can induce hypocalcemia. In such cases, treatment should consist in correcting the hypocalcemia by means of an adequate dietary supplement or, in severe cases, by intravenous administration of calcium.
Should alterations in renal function occur due to the formation of calcium aggregates, following intravenous administration, the therapy must aim at restoring the functionality itself.
Symptoms
Increased serum creatinine and renal dysfunction have been reported with high doses of clodronate administered intravenously.
Treatment
Treatment of overdose should be symptomatic. Adequate hydration should be ensured, and renal function and serum calcium monitored.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Disodium clodronate belongs to the category of diphosphonates, drugs capable of inhibiting the formation and dissolution of hydroxyapatite crystals. Pharmacological and clinical investigations have shown the remarkable inhibitory effect of clodronate disodium on bone resorption, inhibiting osteoclastic activity in all experimental and clinical conditions in which this is exaggeratedly increased.
These conditions include neoplastic diseases such as bone metastases and multiple myeloma, endocrinopathies such as primary hyperparathyroidism, as well as metabolic osteopathies such as immobilization osteopenia and, in particular, postmenopausal osteoporosis.
The efficacy of clodronate disodium in the treatment of hypercalcemic crises was also of particular importance.
Recent research has demonstrated the efficacy of the drug in reducing skeletal morbidity secondary to malignant neoplasms, particularly in breast cancer.
Finally, the analgesic effect of the drug in the treatment of pain secondary to bone metastases, an effect that is established from the first days of intravenous treatment, is also relevant.
Prolonged use of the drug does not induce bone mineralization defects, as confirmed by biopsy investigations.
05.2 Pharmacokinetic properties
Disodiodichloromethylenediphosphonate is rapidly cleared from the body in the urine.
05.3 Preclinical safety data
The acute toxicity of disodiodichloromethylenediphosphonate was found to be remarkably low.
Rat: LD50 1700 mg / kg os; 430 mg / kg e.p .; 65 mg / Kg i.v.
Chronic toxicity: per os in rats, up to 200 mg / kg / day for over 6 months, no toxic effect; per os in the dog, up to 40 mg / kg / day for over 6 months, no toxic effect.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium bicarbonate, water for injections.
06.2 Incompatibility
Incompatible with alkaline solutions or oxidizing solutions.
Clodronate forms complexes with divalent ions and therefore must not be mixed with calcium-containing solutions (e.g. Ringer's solutions).
06.3 Period of validity
2 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Carton containing 6 vials of 100 mg / 3.3 ml of colorless neutral glass.
Carton containing 12 vials of 100 mg / 3.3 ml of colorless neutral glass.
Carton containing 6 vials of 300 mg / 10 ml of colorless neutral glass.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
ABC Farmaceutici S.p.A
Corso Vittorio Emanuele II 72
Turin
08.0 MARKETING AUTHORIZATION NUMBER
AIC n. 035129016 - 100 MG / 3.3 ML SOLUTION FOR INJECTION 6 VIALS OF 3.3 ML
AIC n. 035129028 - 100 MG / 3.3 ML SOLUTION FOR INJECTION 12 VIALS OF 3.3 ML
AIC n. 035129030 - 300 MG / 10 ML SOLUTION FOR INTRAVENOUS INFUSION 6 VIALS
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
November 14, 2001
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 10 October 2012
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