Active ingredients: Clodronic acid
CLODY 300 mg / 10 ml concentrate for solution for infusion
Why is Clody used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Drugs acting on bone structure and mineralization - Bisphosphonates.
THERAPEUTIC INDICATIONS
Tumor osteolysis. Multiple myeloma. Primary hyperparathyroidism.
Contraindications When Clody should not be used
Hypersensitivity to the active substance or to any of the excipients.
Concurrent treatments with other bisphosphonates
Precautions for use What you need to know before taking Clody
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 "Undesirable effects").
Clodronate should be used with caution in patients with renal insufficiency (see dosage adjustments under "Dose, method and time of administration").
Intravenous administration of significantly higher than recommended doses can cause severe kidney damage, especially if the infusion rate is too high.
Interactions Which drugs or foods can change the effect of Clody
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
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).
From a chemical point of view, the contents of the ampoules are incompatible with alkaline solutions or oxidizing solutions.
Warnings It is important to know that:
Osteonecrosis of the jaw, usually associated with tooth extraction and / or local infection (including osteomyelitis), has been reported in cancer patients treated with 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 treatment with bisphosphonates 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 and during treatment should be considered. , these patients should, if possible, avoid invasive dental procedures. In patients who develop 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. Clinical judgment of the physician should guide the management program of each. patient, based on the individual risk / benefit assessment.
Important information about some of the ingredients
Clody 300 mg / 10 ml concentrate for solution for infusion contains 49.1 mg of sodium per dose. To be taken into consideration in people with reduced kidney function or on a low sodium diet.
Fertility, pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
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
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. There is only a limited amount of data on the use of clodronate in pregnant women. Clody is not recommended during pregnancy and in women of childbearing potential not protected 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 Clody treatment.
Effects on ability to drive and use machines.
The product has no effect on the ability to drive and use machines.
Dosage and method of use How to use Clody: Dosage
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.
The following dosing schedule should be considered indicative and can therefore be adapted to the needs of the individual patient.
In the attack phase CLODY 300 mg / 10 ml concentrate for solution for infusion is used: 1 ampoule per day in a single slow intravenous administration for 3-8 days in relation to the trend of clinical and laboratory parameters (calcemia, hydroxyprolinuria, etc.).
In the maintenance phase, CLODY 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine (1 ampoule per day for 2-3 weeks) is recommended.
These treatment 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.
CLODY 300 mg / 10 ml concentrate for solution for infusion is for intravenous use only and must be diluted prior to administration with 0.9% sodium chloride solution.
The medicine is incompatible with alkaline solutions or oxidizing solutions.
- Patients with renal insufficiency
It is recommended that the dosage of the clodronate infusion be reduced as follows:
It is recommended that 300 mg of clodronate be infused prior to hemodialysis, that the dose be reduced by 50% on dialysis-free days, and that the treatment schedule be limited to 5 days. Note that peritoneal dialysis removes clodronate poorly. from circulation.
Overdose What to do if you have taken too much Clody
- Symptoms
Increased serum creatinine and renal dysfunction have been reported with high doses of clodronate administered intravenously. One case of uremia and liver damage has been reported following the accidental ingestion of 20,000 mg (50X400 mg) of clodronate.
- Treatment
Treatment of overdose should be symptomatic. Adequate hydration should be ensured, and renal function and serum calcium monitored.
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, therapy must aim at restoring the function itself. In case of accidental intake of an excessive dose of CLODY, notify your doctor immediately or go to the nearest hospital.
If you have any questions about the use of CLODY, ask your doctor or pharmacist.
Side Effects What are the side effects of Clody
Like all medicines, CLODY can cause side effects, although not everybody gets them.
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.
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.
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
Post-marketing experience
- 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).
- 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 dosage instructions see "Dose, method and time of administration", 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 "Special warnings"). Severe bone, joint and / or muscle pain has been reported in patients taking clodronate disodium. However, such reports have been infrequent and, in randomized placebo-controlled trials, there is no difference between patients treated with placebo or with clodronate disodium. The onset of symptoms varies from days to several months after initiation of disodium clodronate therapy.
The following reactions have been reported during post-marketing experience (frequency rare): atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety of this medicine.
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 dispose of medicines you no longer use. This will help protect the environment.
KEEP THIS MEDICINAL PRODUCT OUT OF THE SIGHT AND REACH OF CHILDREN
COMPOSITION
Each vial contains:
Active principle:
Disodium clodronate (disodium salt of clodronic acid) tetrahydrate mg 374.7 equal to disodium clodronate anhydrous mg 300
Excipients: sodium bicarbonate, water for injections.
PHARMACEUTICAL FORM AND CONTENT
300 mg / 10 ml Concentrate for solution for infusion. Box of 6 vials
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
CLODY 300 MG / 10 ML
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains
Active principle:
disodium clodronate (disodium salt of clodronic acid) tetrahydrate 374.7 mg equal to anhydrous disodium clodronate 300 mg.
Excipients with known effects: sodium.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Concentrate for solution for infusion.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Tumor osteolysis.
Multiple myeloma.
Primary hyperparathyroidism.
04.2 Posology and method of administration
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.
The following dosing schedule should be considered indicative and can therefore be adapted to the needs of the individual patient.
In the attack phase, CLODY 300 mg / 10 ml concentrate for solution for infusion is used: 1 ampoule per day in a single administration intravenously slowly for 3-8 days in relation to the progress of clinical and laboratory parameters (calcemia, hydroxyprolinuria, etc.).
In the maintenance phase, CLODY 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine (1 ampoule per day for 2-3 weeks) is recommended.
These treatment 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.
CLODY 300 mg / 10 ml concentrate for solution for infusion is for intravenous use only.
For more details concerning the preparation of the solution, see section 6.6 Special precautions for disposal and handling.
• Patients with renal insufficiency
It is recommended that the dosage of the clodronate infusion be reduced as follows:
It is recommended that 300 mg of clodronate be infused prior to hemodialysis, that the dose be reduced by 50% on dialysis-free days, and that the treatment schedule be limited to 5 days. Note that peritoneal dialysis removes clodronate poorly. from circulation.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients, listed in section 6.1.
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 "Posology 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.
Osteonecrosis of the jaw, usually associated with tooth extraction and / or local infection (including osteomyelitis), has been reported in cancer patients treated with 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 treatment with bisphosphonates 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, and during treatment, these patients should, if possible, avoid invasive dental procedures.
In patients who develop 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 and / or 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 pain in the thigh or groin, often associated with imaging findings and radiographic evidence of stress fractures, weeks or months before the onset of a stress fracture. 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. Discontinuation of bisphosphonate therapy should be considered in patients with suspected atypical femoral fracture pending evaluation of the patient based on individual benefit risk. Patients should be advised to report any thigh pain during bisphosphonate treatment. hip or groin and any patient who exhibits such symptoms should be evaluated for an incomplete fracture of the femur.
Important information about some of the ingredients
Clody 300 mg / 10 ml concentrate for solution for infusion contains 49.1 mg of sodium per dose.
To be taken into consideration in people with reduced kidney function or who follow a low sodium diet.
04.5 Interactions with other medicinal products and other forms of interaction
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 lactation
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. There is only a limited amount of data on the use of clodronate in pregnant women. Clody is not recommended during pregnancy and in women of childbearing potential not protected 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 Clody treatment.
04.7 Effects on ability to drive and use machines
The drug has no effect on the ability to drive and use machines.
04.8 Undesirable effects
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.
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.
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
Post-marketing experience
• 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).
• 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 (increase in serum creatinine and proteinuria), severe renal damage especially after rapid intravenous infusion of high doses of clodronate (for instructions on posology see section 4.2 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
Isolated cases of osteonecrosis of the jaw have been reported, 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 clodronate disodium. However, such reports have been infrequent and, in randomized placebo-controlled trials, there is no difference between patients treated with placebo or with clodronate disodium. The onset of symptoms varies from days to several months after initiation of disodium clodronate therapy.
The following reactions have been reported during post-marketing experience (frequency rare): atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).
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. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
• Symptoms
Increased serum creatinine and renal dysfunction have been reported with high doses of clodronate administered intravenously. One case of uremia and liver damage has been reported following the accidental ingestion of 20,000 mg (50X400 mg) of clodronate.
• Treatment
Treatment of overdose should be symptomatic. Adequate hydration should be ensured, and renal function and serum calcium monitored.
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, therapy must aim at restoring the function itself.
For the effects due to lidocaine overdose see par. 4.4.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: drugs that affect bone structure and mineralization.
ATC code: M05BA02.
Clodronic acid belongs to the category of bisphosphonates, drugs capable of inhibiting the formation and dissolution of hydroxyapatite crystals. Pharmacological and clinical investigations have demonstrated the remarkable inhibitory effect of disodium clodronate on bone resorption, consequent to the inhibition of 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 episodes 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 treatment, particularly intravenously, is also relevant.
Prolonged use of the drug does not induce bone mineralization defects, as confirmed by biopsy investigations.
05.2 Pharmacokinetic properties
The absorption of disodium clodronate after oral administration is very low, in man it is of the order of 2%. Disodiodichloromethylenediphosphonate is rapidly removed from the organism; 90% of the absorbed dose is found in the urine in unmetabolized form in the first 24 hours after administration.
05.3 Preclinical safety data
The acute toxicity of disodium dichloromethylenediphosphonate 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
The medicine is incompatible with alkaline solutions or oxidizing 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
10 ml type I colorless neutral glass vials, housed in a pre-formed polystyrene box, which in turn is enclosed, together with the package leaflet, in a lithographed cardboard box.
Box of 6 vials of 10 ml.
06.6 Instructions for use and handling
No special instructions for disposal.
CLODY 300 mg / 10 ml concentrate for solution for infusion is for intravenous use only and must be diluted prior to administration with 0.9% sodium chloride solution.
07.0 MARKETING AUTHORIZATION HOLDER
PROMEDICA S.r.l. - Via Palermo 26 / A - PARMA
08.0 MARKETING AUTHORIZATION NUMBER
CLODY 300 mg / 10 ml concentrate for solution for infusion - 6 ampoules of 10 ml AIC: 034294037
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
January 27, 2000
10.0 DATE OF REVISION OF THE TEXT
July 2014
