Clodron

PATIENT INFORMATION LEAFLET

CLODRON 400 mg hard capsules

Clodronic acid
Please read this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

1. What CLODRON is and what it is used for
2. What you need to know before taking CLODRON
3. How to take CLODRON
4. Possible side effects
5. How to store CLODRON
6. Contents of the pack and other information

1. What CLODRON is and what it is used for

CLODRON is a medicine containing clodronic acid, an active substance belonging to a group
of drugs used to treat bone diseases, called bisphosphonates.
CLODRON is used in adults for the treatment:

• of bone weakening due to cancer (tumour-induced osteolysis);
• of bone marrow cancer (multiple myeloma);
• of overactivity of the parathyroid glands (primary hyperparathyroidism). It is also used in women for the prevention and treatment of bone weakening (osteoporosis) after the menopause (the period of permanent cessation of menstruation).

2. What you need to know before taking CLODRON

Do not take CLODRON

• If you are allergic to clodronic acid or to any of the other ingredients of this medicine (listed in section 6).
• If you are taking other bisphosphonates, medicines similar to CLODRON.

Warnings and precautions
Talk to your doctor or pharmacist before taking CLODRON.
Before and during treatment, your doctor will ask you to undergo blood tests to monitor kidney and liver function (see section 4. Possible side effects). It is important that you drink an adequate amount of fluids during treatment with this medicine, especially if you have kidney problems (see section 3. How to take CLODRON).
In particular, inform your doctor:

• If you have high levels of calcium in your blood.
• If you have a kidney disease (renal failure).
• If you are being treated with CLODRON for cancer or osteoporosis and are undergoing dental treatment or need dental surgery. You must also inform your dentist that you are being treated with CLODRON (see section 4. Possible side effects), as preventive dental treatment may be necessary.
• If you have a liver disease.
• If during treatment you experience weakness or pain in the thigh, hip, or groin, as this could be an early sign of a possible femur fracture (see section 4. Possible side effects).
• If you or someone in your family has or has had disorders of the oesophagus (the tube connecting the throat to the stomach) causing delayed passage of food or delayed stomach emptying, or if you suffer from stomach disorders. Your doctor will ask you to pay attention to the administration instructions and to be alert for any signs or symptoms indicating a possible reaction affecting the oesophagus. If you develop symptoms of oesophageal irritation (e.g. difficulty swallowing (dysphagia), painful swallowing, retrosternal pain, or onset/worsening of heartburn), contact your doctor immediately.
• If you have difficulty remaining upright for at least 30 minutes after taking the capsule.

Children and adolescents
The safety and efficacy of this medicine in paediatric patients have not been established.
Other medicines and CLODRON
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
This is particularly important if:

• You are taking other bisphosphonates, medicines used to treat bone diseases, as concomitant use of CLODRON with other bisphosphonates is contraindicated (see section 2. Do not use CLODRON).
• You are taking non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to treat inflammation (particularly diclofenac), as kidney problems may occur.
• You are taking aminoglycosides, medicines used to treat infections, as levels of calcium in the blood may decrease (hypocalcaemia).
• You are taking estramustine, a medicine used to treat prostate cancer (a gland in men that produces seminal fluid), as blood concentrations of estramustine may increase.
• You are taking medicines containing bivalent cations (e.g. mineral supplements, antacids or iron-containing preparations). In such cases, your doctor will advise you to take CLODRON at least 2–3 hours apart.

CLODRON with food and drink
Inform your doctor or pharmacist if you are consuming foods or drinks containing bivalent cations (e.g. foods or drinks containing iron, magnesium, aluminium, calcium) (see section 3. How to take CLODRON).
CLODRON 400 mg hard capsules must be taken at least 2–3 hours apart from foods and/or drinks containing bivalent cations.
Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
Avoid taking CLODRON during pregnancy and if you are of childbearing age and not using an effective contraceptive method (medicines used to prevent pregnancy).
Breastfeeding
It is not known whether clodronic acid passes into breast milk. Therefore, discontinue breastfeeding during treatment with CLODRON.
Fertility
It is not known whether clodronic acid has effects on human fertility.
Driving and using machines
CLODRON may cause visual disturbances that could affect your ability to drive or operate machinery.
If you experience one or more of the symptoms listed in section 4 or if you take more CLODRON than you should, avoid driving and using machinery.
CLODRON contains sodium
CLODRON 400 mg hard capsules contain 64.13 mg of sodium (a main component of table salt) per capsule. This corresponds to 3.2% of the maximum daily dietary intake recommended for an adult.
Talk to your doctor or pharmacist if you need to take 7 or more capsules per day for a prolonged period, especially if you have been advised to follow a low-sodium diet or if you have kidney disease.

3. How to take CLODRON

Take this medicine exactly as directed by your doctor, who will determine the correct dose based on the severity of your condition and the duration of treatment. If you have any doubts, consult your doctor or pharmacist (see the section DOSAGE, METHOD AND DURATION OF ADMINISTRATION at the end of this Patient Information Leaflet).
Clodronic acid is primarily eliminated via the kidneys. Therefore, during treatment with clodronic acid, it is necessary to drink an adequate amount of fluids.

Tumoral osteolysis. Multiple myeloma. Primary hyperparathyroidism.
a) Initial treatment phase
For the initial phase, your doctor will administer CLODRON 300 mg/10 ml concentrate for solution for infusion at a dose of 300 mg/day as a single intravenous slow infusion over 3-8 days, depending on the clinical and laboratory parameters (serum calcium, hydroxyprolinuria, etc.).
For further information on CLODRON 300 mg/10 ml concentrate for solution for infusion, please refer to the corresponding Patient Information Leaflet.

b) Maintenance phase
If your doctor prescribes CLODRON capsules, the recommended dose is 4 capsules daily, taken as a single dose. If your doctor prescribes a higher dose, up to a maximum of 8 capsules per day, the additional dose beyond 4 capsules should be taken separately (as a second dose). The doses should be taken well apart from meals, for the period determined by your doctor depending on the progression of the disease. If necessary, your doctor may request tests to evaluate the health of your bones.

Alternatively, your doctor may administer CLODRON 100 mg + 33 mg injectable solution with lidocaine intramuscularly at a dose of 100 mg/day for 2-3 weeks, according to the instructions described in the corresponding Patient Information Leaflet.

Your doctor will reduce your dose of CLODRON if you have kidney disease.

Prevention and treatment of postmenopausal osteoporosis
The recommended dose is 1 capsule daily for 30 days, followed by a 60-day treatment break (for multiple cycles), up to 1 capsule daily continuously for 1 year or longer, depending on your doctor's prescription.

Alternatively, your doctor may administer CLODRON 100 mg + 33 mg injectable solution with lidocaine intramuscularly (100 mg every 7-14 days) for 1 year or longer, depending on your condition and according to the instructions in the corresponding Patient Information Leaflet, or CLODRON 200 mg + 40 mg injectable solution with lidocaine (200 mg every 14-28 days) for 1 year or longer, depending on your condition and according to the instructions in the corresponding Patient Information Leaflet.

Your doctor will reduce your dose of CLODRON if you have kidney disease.

How to take the capsules
Take the capsules orally with a small amount of water and swallow without chewing.
CLODRON 400 mg capsules must be swallowed whole, preferably in the morning, on an empty stomach, with a glass of water. Do not eat, drink, or take any other oral medicines for one hour after taking the capsule. After swallowing the medicine, do not lie down for 30 minutes.

Under no circumstances should you take the capsules with milk, food, or medicines containing calcium or other bivalent cations (e.g., iron, magnesium, aluminium), as these substances interfere with clodronate absorption. Some mineral waters may have a high calcium content and therefore should not be used.

Exclusively for the treatment of tumoral osteolysis, multiple myeloma, and primary hyperparathyroidism, if multiple daily doses are prescribed, the additional dose must be taken between meals, at least two hours after or one hour before eating, drinking (except plain water), or taking other oral medicines.

If you take more CLODRON than you should
In case of accidental overdose, contact your doctor or the nearest hospital immediately.
Symptoms of overdose may include:

• increased blood creatinine levels and kidney disease (renal dysfunction) (with high doses of intravenous clodronic acid)
• elevated blood nitrogen levels (uremia)
• liver damage
• low blood calcium levels (hypocalcemia)

Treatment
Your doctor will manage symptoms with appropriate specific therapies.

If you forget to take CLODRON
Do not take a double dose to make up for a missed capsule.

If you stop taking CLODRON
If you have any doubts about using this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
If you experience any visual disturbances or eye problems during treatment, STOP taking the medicine and consult an ophthalmologist immediately.
Inform your doctor immediately if you experience:

• pain or sores in the mouth or jaw and/or maxilla (two facial bones), as these may be early signs of serious problems (bone necrosis of the jaw and/or maxilla), generally associated with tooth extraction and/or local infection (see section 2. Warnings and precautions).

The possible side effects listed below are categorized by frequency:
Common (may affect up to 1 in 10 people)

• decreased blood calcium levels without symptoms (asymptomatic hypocalcemia),
• diarrhoea, nausea, vomiting (usually mild in intensity),
• increased transaminase levels in the blood (a test to assess liver function), usually within normal ranges.

Rare (may affect up to 1 in 1,000 people)

• decreased blood calcium levels with symptoms (symptomatic hypocalcemia),
• increased parathyroid hormone levels (a hormone that regulates blood calcium levels) associated with low blood calcium,
• increased alkaline phosphatase levels in the blood (a test to assess bone and liver condition),
• increased transaminase levels in the blood (a test to assess liver function) more than twice the upper normal limit, without other signs of liver dysfunction,
• allergic reactions manifesting as skin reactions,
• unusual femur fracture (long bone of the leg), particularly in patients undergoing long-term treatment for osteoporosis. Contact your doctor if you experience pain or weakness in the thigh, hip, or groin, as this could be an early sign of a possible femur fracture.

Very rare (may affect up to 1 in 10,000 people)

• consult your doctor if you experience ear pain, ear discharge, and/or ear infection. These events could be symptoms of bone damage in the ear.

The following side effects may also occur, for which the frequency cannot be estimated from the available data:

• Effects related to the eyes

  • inflammation of the conjunctiva, the membrane covering the eye and the inner surface of the eyelids (conjunctivitis);
  • eye inflammation (episcleritis, scleritis, and uveitis). Episcleritis and scleritis have been reported with other drugs in the same class as clodronic acid (a class-effect of bisphosphonates).

• Effects related to the lungs

  • breathing difficulties in patients with aspirin-sensitive asthma (a medicine used to treat fever, pain, and inflammation);
  • allergic reactions manifesting as respiratory problems.

• Effects related to the kidneys and urinary tract

  • kidney disease (renal failure), severe kidney damage. Rarely, and especially in association with the use of NSAIDs (medicines used to treat inflammation and pain), renal failure has led to death (more frequently with diclofenac). See section 2. Other medicines and CLODRON.

• Effects related to bones and muscles

  • severe bone, joint, and muscle pain. Onset of symptoms varies from days to several months after starting CLODRON therapy;
  • pain or sores in the mouth or jaw and/or maxilla (two facial bones). These may be early signs of serious problems (bone necrosis of the jaw and/or maxilla), generally associated with tooth extraction and/or local infection (see section 2. Warnings and precautions). In most cases, this has occurred in cancer patients.

• Effects related to the stomach and intestines

  • inflammation or irritation of the oesophagus, the tube connecting the pharynx to the stomach (oesophagitis);
  • stomach inflammation (gastritis);
  • oesophageal lesions (oesophageal ulcers);
  • stomach and intestinal lesions (gastroduodenal ulcers).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects 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 the safety of this medicine.

5. How to store CLODRON

This medicine does not require any special storage conditions.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the packaging after Exp.
The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of
medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What CLODRON 400 mg hard capsules contains

• The active substance is Disodium clodronate (disodium salt of clodronic acid) 400 mg
• The other components are sodium starch glycolate (type A), corn starch, talc, magnesium stearate. Capsule shell components: gelatin, titanium dioxide (E 171), indigotine (E 132).

Description of the appearance of CLODRON and contents of the pack
CLODRON 400 mg hard capsules is available in packages containing blisters of 10 capsules.
Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
ABIOGEN PHARMA S.p.A. - Via Meucci, 36 - Ospedaletto – Pisa – Italy
Manufacturer
ABIOGEN PHARMA S.p.A. – Via Meucci 36 – Ospedaletto – Pisa

---

The following information is intended exclusively for physicians or healthcare professionals:
DOSAGE, METHOD AND DURATION OF ADMINISTRATION
Tumoral osteolysis. Multiple myeloma. Primary hyperparathyroidism.
The following dosage regimen is indicative and may therefore be adjusted according to the individual patient's needs.
a) Initial phase
CLODRON 300 mg/10 ml concentrate for solution for infusion, 300 mg/day as a single intravenous slow infusion over 3-8 days, depending on the clinical and laboratory parameters (calcemia, hydroxyprolinuria, etc.).
For further information on CLODRON 300 mg/10 ml concentrate for solution for infusion, see the corresponding Summary of Product Characteristics and Package Leaflet.
b) Maintenance phase
CLODRON 100 mg + 33 mg injectable solution with lidocaine, 100 mg/day administered intramuscularly for 2-3 weeks. For further information on CLODRON 100 mg + 33 mg injectable solution with lidocaine, see the corresponding Summary of Product Characteristics and Package Leaflet.
Alternatively
CLODRON 400 mg hard capsules, 4 capsules/day (1600 mg of sodium clodronate). If necessary, the dose may be increased, but must not exceed a maximum of 8 capsules/day (3200 mg of sodium clodronate). The daily dose of 1600 mg should be taken as a single dose. When higher doses are used, the amount exceeding 1600 mg should be taken separately (as a second dose). Doses must be administered apart from meals.
The duration of treatment, usually long-term, depends on the progression of the disease.
Periodic re-evaluation of bone resorption parameters is recommended as a guide to assess the need for continuing therapy.

Prevention and treatment of postmenopausal osteoporosis.
Dosage, depending on clinical condition and mineralometric values, may vary as follows:
Oral therapy
CLODRON 400 mg hard capsules, 1 capsule/day × 30 days, followed by a 60-day treatment interruption (for multiple cycles), up to 1 capsule/day continuously for 1 year or longer, depending on the patient's condition.

Method of administration
CLODRON 400 mg capsules must be swallowed whole. The daily dose should preferably be taken in the morning on an empty stomach with a glass of water. The patient must then refrain from eating, drinking (except plain water) or taking other oral medications for one hour after administration. After taking the medicine, patients are advised not to lie down for 30 minutes.
Under no circumstances should clodronate be taken with milk, food, or medications containing calcium or other bivalent cations, as these substances interfere with clodronate absorption. Some mineral waters may have a high calcium concentration and therefore should not be used.
Exclusively for the treatment of tumoral osteolysis, multiple myeloma, and primary hyperparathyroidism, when multiple daily doses are required, the additional dose should be taken between meals, at least two hours after or one hour before eating, drinking (except plain water), or taking other oral medications.

Parenteral therapy
CLODRON 100 mg + 33 mg injectable solution with lidocaine
intramuscularly, 100 mg every 7-14 days, for 1 year or longer depending on the patient's condition.
CLODRON 200 mg + 40 mg injectable solution with lidocaine
intramuscularly, 200 mg every 14-28 days, for 1 year or longer depending on the patient's condition.
For further information on CLODRON 100 mg + 33 mg injectable solution with lidocaine and CLODRON 200 mg + 40 mg injectable solution with lidocaine, see the corresponding Summary of Product Characteristics and Package Leaflet.
The duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be periodically reassessed for each individual patient based on benefits and potential risks, particularly after 5 or more years of use.

• Children: The safety and efficacy of the drug in pediatric patients have not been established.
• Elderly: No specific dosage recommendations for the elderly are required. Clinical studies have included patients over 65 years of age, and no age-specific adverse events have been reported.
• Patients with renal impairment – Oral administration: Clodronate is primarily eliminated via the kidneys. Therefore, it must be used with caution in patients with renal impairment. Daily doses exceeding 1600 mg should not be used continuously. It is recommended to reduce the clodronate dosage as follows:

PATIENT INFORMATION LEAFLET

CLODRON 300 mg/10 ml concentrate for solution for infusion

Clodronic acid
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

1. What CLODRON is and what it is used for
2. What you need to know before using CLODRON
3. How to use CLODRON
4. Possible side effects
5. How to store CLODRON
6. Contents of the pack and other information

1. What CLODRON is and what it is used for

CLODRON is a medicine containing clodronic acid, an active substance belonging to a group
of drugs used to treat bone diseases, called bisphosphonates.
CLODRON is used in adults for the treatment of:

• bone weakening due to cancer (tumour-induced osteolysis);
• bone marrow cancer (multiple myeloma);
• overactivity of the parathyroid glands (primary hyperparathyroidism).

2. What you should know before using CLODRON

Do not use CLODRON

• If you are allergic to clodronic acid or to any of the other ingredients of this medicine (listed in section 6).
• If you are taking other bisphosphonates, medicines similar to CLODRON.

Warnings and precautions
Talk to your doctor or pharmacist before using CLODRON.
Before and during treatment, your doctor will ask you to undergo blood tests to monitor kidney and liver function (see section 4. Possible side effects). It is important that you drink an adequate amount of fluids during treatment with this medicine, especially if you have kidney problems (see section 3. How to use CLODRON).
In particular, inform your doctor:

• If you have high levels of calcium in your blood.
• If you suffer from kidney disease (renal insufficiency).
• If you are being treated with CLODRON for cancer and are currently undergoing dental treatment or need to undergo dental surgery. You should also inform your dentist that you are being treated with CLODRON (see section 4. Possible side effects), as preventive dental treatment may be necessary.
• If you suffer from liver disease.
• If during treatment you experience weakness or pain in the thigh, hip, or groin, as this could be an early sign of a possible femoral fracture (see section 4. Possible side effects).

Children and adolescents
The safety and efficacy of this medicine in pediatric patients have not been established.
Other medicines and CLODRON
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
This is particularly important if:

• You are taking other bisphosphonates, medicines used to treat bone diseases, since concomitant use of CLODRON with other bisphosphonates is contraindicated (see section 2. Do not use CLODRON).
• You are taking non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to treat inflammation (especially diclofenac), as kidney problems may occur.
• You are taking aminoglycosides, medicines used to treat infections, as calcium levels in the blood may decrease (hypocalcemia).
• You are taking estramustine, a medicine used to treat prostate cancer (a gland in men that produces seminal fluid), as blood levels of estramustine may increase.
• You are receiving intravenous solutions containing bivalent cations (e.g., Ringer's solution).

Pregnancy, breastfeeding and fertility
If you are pregnant, think you might be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before this medicine is administered.
Pregnancy
Avoid using CLODRON during pregnancy and if you are of childbearing age and not using effective contraception (medicines used to prevent pregnancy).
Breastfeeding
It is not known whether clodronic acid passes into breast milk. Therefore, during treatment with CLODRON, discontinue breastfeeding.
Fertility
It is not known whether clodronic acid has effects on human fertility.
Driving and operating machinery
CLODRON may cause visual disturbances that could affect your ability to drive or operate machinery.
If you experience one or more of the symptoms listed in section 4 or if you take more CLODRON than you should, avoid driving and operating machinery.
CLODRON contains sodium
This medicine contains 48.89 mg of sodium (main component of table salt) per dose. This corresponds to 2.46% of the maximum daily recommended dietary intake for an adult.
This should be taken into consideration if you suffer from kidney disease or are on a low-sodium diet.

3. How to use CLODRON

Use this medicine exactly as directed by your doctor, who will determine the correct dose according to the severity of your condition and the duration of treatment. This medicine will be administered to you by a doctor or nurse (see the section DOSAGE, METHOD AND DURATION OF ADMINISTRATION at the end of this Patient Information Leaflet).
Clodronic acid is primarily eliminated via the kidneys. Therefore, during treatment with clodronic acid, you must drink an adequate amount of fluids.
This is particularly important when CLODRON is administered to you intravenously:

• if you have high levels of calcium in the blood
• if you have kidney disease (renal insufficiency).

Method of administration
CLODRON 300 mg/10 ml concentrate for solution for infusion is for intravenous use only and must be diluted before infusion. It will be administered slowly (2–3 hours) directly into your vein.
If you use more CLODRON than you should
If you accidentally take too much CLODRON, contact your doctor or go to the nearest hospital immediately.
Symptoms of overdose may include:

• increased creatinine levels in the blood and kidney disease (renal dysfunction) (with high doses of clodronic acid administered intravenously)
• elevated blood nitrogen levels (uraemia)
• liver damage
• low calcium levels in the blood (hypocalcaemia)

Treatment: Your doctor will manage the symptoms with appropriate specific therapies.

If you forget to use CLODRON
Do not take a double dose to make up for the missed dose.
If you stop using CLODRON
If you have any doubts about using this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
If you experience any visual disturbances or eye problems during treatment, STOP the treatment immediately and consult an ophthalmologist.
Inform your doctor immediately if you experience:

• pain or sores in the mouth or jaw and/or maxilla (two facial bones), as these may be early signs of serious problems (bone necrosis of the jaw and/or maxilla), usually associated with tooth extraction and/or local infection (see section 2. Warnings and precautions).

The possible side effects listed below are categorized by frequency:

Common (may affect up to 1 in 10 people)

• decrease in blood calcium levels without symptoms (asymptomatic hypocalcaemia),
• diarrhoea, nausea, vomiting (usually mild in intensity),
• increased transaminase levels in the blood (a test to assess liver function), usually within normal limits.

Rare (may affect up to 1 in 1,000 people)

• decrease in blood calcium levels with symptoms (symptomatic hypocalcaemia),
• increased parathyroid hormone levels (a hormone that regulates calcium levels in the blood) associated with low blood calcium,
• increased alkaline phosphatase levels in the blood (a test to assess bone and liver condition),
• increased transaminase levels in the blood (a test to assess liver function) more than twice the upper normal limit, without other signs of liver dysfunction,
• allergic reactions manifesting as skin reactions,
• unusual femur fracture (long bone of the leg), particularly in patients undergoing long-term treatment for osteoporosis. Contact your doctor if you experience pain or weakness in the thigh, hip, or groin, as this could be an early sign of a possible femur fracture.

Very rare (may affect up to 1 in 10,000 people)

• consult your doctor if you experience ear pain, ear discharge, and/or ear infection. These events could be symptoms of bone damage in the ear.

The following side effects may also occur, for which frequency cannot be estimated:

• effects related to the eyes

  • inflammation of the conjunctiva, the membrane covering the eye and the inner surface of the eyelids (conjunctivitis);
  • inflammation of the eye (episcleritis, scleritis, and uveitis). Episcleritis and scleritis have been reported with other drugs belonging to the same class as clodronic acid (a class effect of bisphosphonates).

• effects related to the lungs

  • breathing difficulties in patients with asthma sensitive to acetylsalicylic acid (a medicine used to treat fever, pain, and inflammation);
  • allergic reactions manifesting as respiratory problems.

• effects related to the kidneys and urinary tract

  • kidney disease (renal failure), severe kidney damage. Rarely, and especially in association with the use of NSAIDs (medicines used to treat inflammation and pain), renal failure has led to death (more frequently with diclofenac). See section 2. Other medicines and CLODRON.

• effects related to bones and muscles

  • severe bone, joint, and muscle pain. Onset of symptoms varies from days to several months after starting treatment with CLODRON;
  • pain or sores in the mouth or jaw and/or maxilla (two facial bones). These may be early signs of serious problems (bone necrosis of the jaw and/or maxilla), usually associated with tooth extraction and/or local infection (see section 2. Warnings and precautions). In most cases, this has occurred in cancer patients.

• effects related to the injection site

  • pain or tenderness at the injection site, particularly considering the duration of treatment.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects 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 the safety of this medicine.

5. How to store CLODRON

This medicine does not require any special storage conditions.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton after Exp.
The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of
medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What CLODRON contains CLODRON 300 mg/10 ml concentrate for solution for infusion

• The active substance is Disodium clodronate (disodium salt of clodronic acid) 300 mg
• The other components are: sodium bicarbonate (see section 2. CLODRON contains sodium), water for injections.

Description of the appearance of CLODRON and contents of the pack
CLODRON 300 mg/10 ml concentrate for solution for infusion is available in packs of 6 and 12 vials
for intravenous use.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
ABIOGEN PHARMA S.p.A. - Via Meucci, 36 – Ospedaletto – Pisa – Italy
Manufacturer
ABIOGEN PHARMA S.p.A. – Via Meucci 36 – Ospedaletto – Pisa

---

The following information is intended exclusively for physicians or healthcare professionals:
This medicinal product is for intravenous use only.
Dilute before administration.
The solution is incompatible with alkaline solutions or oxidizing solutions.
DOSAGE, METHOD AND DURATION OF ADMINISTRATION
Tumour-induced osteolysis. Multiple myeloma. Primary hyperparathyroidism.
The following dosage regimen should be considered indicative and may therefore be adjusted according to
the individual patient's needs.
a) Initial phase
CLODRON 300 mg/10 ml concentrate for solution for infusion, 300 mg/ day as a single intravenous
administration over 3–8 days, depending on the clinical and laboratory parameters (serum calcium,
hydroxyprolinuria, etc.).
Clodronate is administered as a slow intravenous infusion of 300 mg (one 10 ml vial)/day diluted in 500 ml
of 0.9% physiological saline (sodium chloride 9 mg/ml) or 5% glucose solution (50 mg/ml). This solution
must be administered by slow intravenous infusion over a period of at least two hours.
b) Maintenance phase
CLODRON 100 mg + 33 mg injectable solution with lidocaine, 100 mg/ day by intramuscular injection for 2–3
weeks. For further information on CLODRON 100 mg + 33 mg injectable solution with lidocaine, refer to the
corresponding Summary of Product Characteristics and Package Leaflet.
Alternatively,
CLODRON 400 mg hard capsules, 4 capsules/ day (1600 mg of disodium clodronate); if necessary, the dose
may be increased but must not exceed a maximum of 8 capsules/ day (3200 mg of disodium clodronate). For
further information on CLODRON 400 mg hard capsules, refer to the corresponding Summary of Product
Characteristics and Package Leaflet.
The duration of treatment, usually long-term, depends on the progression of the disease.
Periodic reassessment of bone resorption parameters is recommended as a guide to determine the need for
continuing therapy.
Special populations

• Children: The safety and efficacy of the drug in paediatric patients have not been established.
• Elderly: There are no specific dosage recommendations for elderly patients. Clinical studies have included patients over 65 years of age, and no age-specific adverse events have been reported in this group.
• Patients with renal impairment: Clodronate is primarily eliminated via the kidneys. Therefore, it should be used with caution in patients with renal impairment.

Parenteral administration
It is recommended to reduce the clodronate dosage as follows:

It is recommended to administer clodronate before hemodialysis, to reduce the dose by 50% on non-dialysis days, and to limit the treatment schedule to 5 days. It should be noted that peritoneal dialysis removes clodronate poorly from the circulation. Intravenous administration of doses considerably higher than those recommended may cause severe renal damage, especially if the infusion rate is too high.
Dilute before administration.
Intravenous administration must be performed by slow infusion (2-3 hours) in 0.9% sodium chloride or 5% glucose solution.
Clodronate forms poorly water-soluble complexes with bivalent cations. Therefore, clodronate must not be administered intravenously with solutions containing bivalent cations (e.g.: Ringer's solution).

PATIENT INFORMATION LEAFLET: INFORMATION FOR THE PATIENT

CLODRON 100 mg + 33 mg injectable solution with lidocaine, 200 mg + 40 mg injectable solution with lidocaine

Clodronic acid - Lidocaine
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, consult your doctor or pharmacist. See section 4.

Contents of this leaflet:

1. What CLODRON is and what it is used for
2. What you need to know before using CLODRON
3. How to use CLODRON
4. Possible side effects
5. How to store CLODRON
6. Contents of the pack and other information

1. What CLODRON is and what it is used for

CLODRON is a medicine that contains clodronic acid, an active substance belonging to a group of drugs used to treat bone diseases called bisphosphonates.
CLODRON is used in adults for the treatment:

• of bone weakening due to cancer (tumour-induced osteolysis);
• of bone marrow cancer (multiple myeloma);
• of overactivity of the parathyroid glands (primary hyperparathyroidism). It is also used in women for the prevention and treatment of bone weakening (osteoporosis) after the menopause (permanent end of menstrual periods).

2. What you need to know before using CLODRON

Do not use CLODRON

• If you are allergic to clodronic acid or to any of the other ingredients of this medicine (listed in section 6).
• If you are taking other bisphosphonates, medicines similar to CLODRON.
• If you are allergic to lidocaine or to other amide-type local anesthetics, such as bupivacaine, mepivacaine, ropivacaine, levobupivacaine.
• If you have a heart condition causing loss of consciousness (Adam-Stokes syndrome).
• If you have a heart rhythm disorder (Wolff-Parkinson-White syndrome, atrial fibrillation, sinoatrial, atrioventricular or intraventricular block).
• If you have weak heart function unable to supply sufficient blood to the body (acute heart failure).
• If you have low blood volume (hypovolemia).

The medicine is for intramuscular use only (i.e. injected into a muscle) and must not be
administered into a blood vessel (intravenously). Accidental injection into a
vein increases the risk of serious adverse reactions due to high blood levels
of the anesthetic lidocaine (see section 3. If you use more CLODRON than you should).
Warnings and precautions
Talk to your doctor or pharmacist before using CLODRON.
Before and during treatment, your doctor will ask you to undergo blood tests to monitor
kidney and liver function (see section 4. Possible side effects). It is important that you drink
adequate amounts of fluids during treatment with this medicine, especially if you have kidney
problems (see section 3. How to use CLODRON).
In particular, inform your doctor:

• If you have high levels of calcium in your blood.
• If you have kidney disease (renal insufficiency).
• If you are being treated with CLODRON for cancer or osteoporosis and are undergoing dental treatment or need dental surgery. Inform your dentist that you are being treated with CLODRON (see section 4. Possible side effects), as preventive dental treatment may be necessary.
• If you have heart disease (especially heart rhythm disorders with slow heart rate and heart failure) or have had heart surgery.
• If you have liver disease.
• If you or a family member has a condition causing high body temperature after using local anesthetics such as lidocaine (familial malignant hyperthermia).
• If you experience thigh, hip or groin pain or weakness during treatment, as this could be an early sign of a possible femoral fracture (see section 4. Possible side effects).
• If you have seizures (epilepsy). Your doctor will closely monitor you for any symptoms.
• If you have respiratory or lung disorders.
• If you have a disease causing muscle weakness (myasthenia gravis).
• If you have porphyria (a rare inherited blood disorder affecting the skin and nervous system).

Children and adolescents
The safety and efficacy of this medicine in pediatric patients have not been established.
Other medicines and CLODRON
Inform your doctor or pharmacist if you are taking, have recently taken or might take any other
medicine.
This is particularly important if:

• You are taking other bisphosphonates, medicines used to treat bone diseases, as concomitant use of CLODRON with other bisphosphonates is contraindicated (see section 2. Do not use CLODRON).

• You are taking non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to treat inflammation (especially diclofenac), as kidney problems may occur.

• You are taking aminoglycosides, medicines used to treat infections, as blood calcium levels may decrease (hypocalcemia).

• You are taking estramustine, a medicine used to treat prostate cancer (a gland in men that produces seminal fluid), as blood levels of estramustine may increase.

• You are taking medicines used to treat heart disorders including irregular heartbeat, such as beta-blockers (e.g. propranolol), calcium channel blockers (e.g. amiodarone) or sodium channel blockers, as lidocaine may remain in circulation longer.

• You are taking cimetidine, a medicine mainly used to treat gastritis and gastric ulcer (a lesion in the stomach wall); fluvoxamine (a medicine used for depression); antiviral medicines such as ritonavir; antibiotics such as macrolide antibiotics (erythromycin) or other antibiotics like ciprofloxacin; antifungal medicines such as ketoconazole, itraconazole, as blood levels of lidocaine may increase.

• You are taking barbiturates such as phenobarbital; medicines used to treat epilepsy such as carbamazepine; phenytoin; primidone; oral contraceptives or hormone replacement therapy, as blood levels of lidocaine may decrease.

• You are being treated with digitalis, medicines used to treat heart rhythm disorders, as the risk of heart rhythm disturbances may increase.

• You are taking muscle relaxants used during general anesthesia, such as suxamethonium. The solution is incompatible with alkaline solutions or oxidizing solutions.

Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, planning to become pregnant, or breastfeeding,
consult your doctor or pharmacist before using this medicine.
Pregnancy
Avoid using CLODRON during pregnancy and if you are of childbearing age and not using effective
contraception (medicines used to prevent pregnancy).
Breastfeeding
It is not known whether clodronic acid passes into breast milk, whereas lidocaine is excreted in breast milk
in small amounts. Therefore, during treatment with CLODRON, breastfeeding should be discontinued.
Fertility
It is not known whether clodronic acid and lidocaine have effects on human fertility.
Driving and using machines
CLODRON may cause visual disturbances that could affect your ability to drive and use machines.
If you experience one or more of the symptoms listed in section 4 or if you use more CLODRON than you should, avoid driving and using machines.
CLODRON contains sodium
CLODRON 100 mg + 33 mg injectable solution with lidocaine contains 17.02 mg of sodium per dose. This
medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially ‘sodium-free’.
CLODRON 200 mg + 40 mg injectable solution with lidocaine contains 32.92 mg of sodium (main
component of table salt) per dose. This corresponds to 2% of the maximum daily recommended dietary
intake for an adult.
This should be taken into account if you have kidney disease or are on a low-sodium diet.

3. How to use CLODRON

Use this medicine exactly as directed by your doctor, who will determine the correct dose for you based on the severity of your condition and the duration of treatment. If you have any doubts, consult your doctor or pharmacist (see the section DOSAGE, METHOD AND DURATION OF ADMINISTRATION at the end of this Patient Information Leaflet).

Clodronic acid is primarily eliminated via the kidneys. Therefore, during treatment with clodronic acid, you must drink an adequate amount of fluids.

Method of administration
CLODRON 100 mg + 33 mg injection solution with lidocaine and CLODRON 200 mg + 40 mg injection solution with lidocaine are for intramuscular use only (i.e., to be injected into a muscle). To avoid accidental injection into a blood vessel, it is recommended to aspirate before injecting the medicine.
Do not massage the injection site.

If you use more CLODRON than you should
If you accidentally take too much CLODRON, contact your doctor or go to the nearest hospital immediately.

Symptoms of overdose may include:

• increased blood creatinine levels and kidney disease (renal dysfunction) (with high doses of clodronic acid administered intravenously),
• elevated blood nitrogen levels (uraemia),
• liver damage,
• low levels of calcium in the blood (hypocalcaemia).

In case of accidental intravascular injection, the following symptoms of lidocaine overdose may occur:

• drowsiness,
• euphoria (state of excessive excitement),
• sedation (physical and mental relaxation),
• loss of sensation in certain parts of the body (paraesthesiae),
• muscle spasms (sudden, involuntary muscle contractions),
• uncontrolled body movements (convulsions),
• reduced blood flow to the body (cardiocirculatory collapse).

Treatment
The doctor will manage the symptoms with specific therapies.

If you forget to use CLODRON
Do not use a double dose to make up for the forgotten dose.

If you stop using CLODRON
If you have any doubts about using this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
If you experience any visual or eye disturbances during treatment, STOP the treatment and consult an ophthalmologist.
Inform your doctor immediately if you experience:

• pain or sores in the mouth or jaw and/or maxilla (two facial bones), as these may be early signs of serious problems (bone necrosis of the jaw and/or maxilla), generally associated with tooth extraction and/or local infection (see section 2. Warnings and precautions).

The possible side effects are listed below by frequency:
Common (may affect up to 1 in 10 people)

• decreased calcium levels in the blood without symptoms (asymptomatic hypocalcaemia),
• diarrhoea, nausea, vomiting (usually mild in intensity),
• increased transaminase levels in the blood (a test to assess liver function), usually within normal values.

Rare (may affect up to 1 in 1,000 people)

• decreased calcium levels in the blood with symptoms (symptomatic hypocalcaemia),
• increased parathyroid hormone levels (a hormone regulating blood calcium levels) associated with low blood calcium,
• increased alkaline phosphatase levels in the blood (a test to assess bone and liver condition),
• increased transaminase levels in the blood (a test to assess liver function) more than twice the upper normal limit, without other liver function abnormalities,
• allergic reactions manifesting as skin reactions,
• unusual femur fracture (long leg bone), particularly in patients receiving long-term treatment for osteoporosis. Contact your doctor if you experience pain or weakness in the thigh, hip, or groin, as this could be an early sign of a possible femur fracture.

Very rare (may affect up to 1 in 10,000 people)

• consult your doctor if you experience ear pain, ear discharge, and/or ear infection. These events could be symptoms of bone damage in the ear.

The following side effects may also occur, for which the frequency cannot be determined:

• Effects related to the eyes
  • inflammation of the conjunctiva, the membrane covering the eye and inner eyelids (conjunctivitis);
  • eye inflammation (episcleritis, scleritis, and uveitis). Episcleritis and scleritis have been reported with other drugs belonging to the same class as clodronic acid (a class adverse reaction of bisphosphonates).
• Effects related to the lungs
  • breathing difficulties in patients with aspirin-sensitive asthma (a medicine used to treat fever, pain, and inflammation);
  • allergic reactions manifesting as respiratory disturbances.
• Effects related to the kidneys and urinary tract
  • kidney disease (renal failure), severe kidney damage. Rarely, and especially in association with the use of NSAIDs (medicines used to treat inflammation and pain), renal failure has led to death (more frequently with concomitant use of diclofenac). See section 2. Other medicines and CLODRON.
• Effects related to bones and muscles
  • severe bone, joint, and muscle pain. The onset of symptoms varies from days to several months after starting treatment with CLODRON;
  • pain or sores in the mouth or jaw and/or maxilla (two facial bones). These may be early signs of serious problems (bone necrosis of the jaw and/or maxilla), generally associated with tooth extraction and/or local infection (see section 2. Warnings and precautions). In most cases, this occurred in cancer patients.
• Effects related to the injection site
  • pain at the injection site, particularly considering the duration of treatment.
• Lidocaine-specific adverse effects
  The following adverse effects are associated with lidocaine. There are insufficient data to determine the frequency of the individual effects listed. Adverse effects are generally due to either allergic reactions or excessively high blood concentrations caused by accidental intravascular injection and/or overdose. This may occasionally cause central nervous system excitation and occasional cardiovascular depression (see section 2. Warnings and precautions).
  Immune system disorders
  Severe allergic reaction (anaphylactoid), swelling of the larynx leading to breathing difficulty (bronchospasm), and drop in blood pressure (cardiorespiratory collapse) due to anaphylactic shock.

Nervous system disorders
Signs of excitation or depression associated with dizziness, drowsiness, visual disturbances, tremors, followed by altered consciousness, seizures, coma, prolonged contraction of the jaw muscles leading to tight closure of the jaw and maxilla (trismus), altered sensation in limbs or other body parts (paraesthesia).

Psychiatric disorders
Anxiety, disorientation.

Cardiac disorders
Reduced heart rate (bradycardia), heart rhythm disturbances (arrhythmias), myocardial depression up to cardiac arrest.

Eye disorders
Pupil dilation (mydriasis), blurred vision, double vision (diplopia).

Gastrointestinal disorders
Nausea, vomiting.

Respiratory, thoracic and mediastinal disorders
Difficulty breathing (dyspnoea), reduced respiratory rate (respiratory depression).

Vascular disorders
Low blood pressure (hypotension), high blood pressure (hypertension), interruption of normal blood circulation due to cardiac arrest and reduced blood flow (circulatory collapse).

Skin and subcutaneous tissue disorders
Sudden skin redness (various types of skin rashes), itchy rash with raised bumps (urticaria), itching.

Ear and labyrinth disorders
Ringing in the ears (tinnitus), increased sensitivity to relatively low sounds (hyperacusis).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects 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 the safety of this medicine.

5. How to store CLODRON

This medicine does not require any special storage conditions.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after Exp.
The expiry date refers to the last day of that month.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What CLODRON contains
CLODRON 100 mg + 33 mg injectable solution with lidocaine

• The active substances are Disodium clodronate (disodium salt of clodronic acid) 100 mg and Lidocaine hydrochloride monohydrate 33 mg.
• The other components are Sodium bicarbonate (see section 2. CLODRON contains sodium), water for injections.

CLODRON 200 mg + 40 mg injectable solution with lidocaine

• The active substances are Disodium clodronate (disodium salt of clodronic acid) 200 mg and Lidocaine hydrochloride monohydrate 40 mg.
• The other components are Sodium bicarbonate (see section 2. CLODRON contains sodium), water for injections.

Description of the appearance of CLODRON and contents of the pack
CLODRON 100 mg + 33 mg injectable solution with lidocaine is available in packs of 6 and 12 vials of colourless neutral glass for intramuscular use.
CLODRON 200 mg + 40 mg injectable solution with lidocaine is available in packs of 3 and 6 vials of colourless neutral glass for intramuscular use.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
ABIOGEN PHARMA S.p.A. - Via Meucci, 36 – Ospedaletto – Pisa – Italy
Manufacturer
ABIOGEN PHARMA S.p.A. – Via Meucci 36 – Ospedaletto – Pisa

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The following information is intended exclusively for physicians or healthcare professionals:
DOSAGE, METHOD AND DURATION OF ADMINISTRATION
Tumoral osteolysis. Multiple myeloma. Primary hyperparathyroidism.
The following dosage regimen is indicative and may therefore be adapted according to the individual patient's needs.
a) Initial phase
CLODRON 300 mg/10 ml concentrate for solution for infusion, 300 mg/day administered as a single slow intravenous infusion for 3-8 days, depending on the clinical and laboratory parameters (serum calcium, hydroxyprolinuria, etc.).
For further information on CLODRON 300 mg/10 ml concentrate for solution for infusion, see the corresponding Summary of Product Characteristics and Package Leaflet.
b) Maintenance phase
CLODRON 100 mg + 33 mg injectable solution with lidocaine, 100 mg/day by intramuscular injection for 2-3 weeks.
Or alternatively,
CLODRON 400 mg hard capsules, 4 capsules/day (1600 mg of sodium clodronate). If necessary, the dose may be increased, but must not exceed a maximum of 8 capsules/day (3200 mg of sodium clodronate). For further information on CLODRON 400 mg hard capsules, see the corresponding Summary of Product Characteristics and Package Leaflet.
The duration of treatment, usually long-term, depends on the progression of the disease.
Periodic re-evaluation of bone resorption parameters is recommended as a guide to assess the need for continuing therapy.

Prevention and treatment of postmenopausal osteoporosis.
Dosage, depending on the clinical picture and bone mineral density values, may vary as follows:
Parenteral therapy
CLODRON 100 mg + 33 mg injectable solution with lidocaine
by intramuscular injection: 100 mg every 7-14 days, for 1 year or longer depending on the patient's condition.
CLODRON 200 mg + 40 mg injectable solution with lidocaine
by intramuscular injection: 200 mg every 14-28 days, for 1 year or longer depending on the patient's condition.
CLODRON 200 mg + 40 mg injectable solution with lidocaine may be used in patients who have never previously received clodronate treatment.
When switching from CLODRON 100 mg + 33 mg to CLODRON 200 mg + 40 mg, administration of one vial of CLODRON 200 mg + 40 mg every 14 days may be used as an alternative dosage regimen in patients already being treated with one 100 mg vial weekly.
Administration of one vial of CLODRON 200 mg + 40 mg every 28 days may be used as an alternative dosage regimen in patients already being treated with one 100 mg vial every two weeks.

Oral therapy
CLODRON 400 mg hard capsules, 1 capsule/day × 30 days, followed by 60 days of treatment interruption (for multiple cycles), up to 1 capsule/day continuously for 1 year or longer depending on the patient's condition. For further information on CLODRON 400 mg hard capsules, see the corresponding Summary of Product Characteristics and Package Leaflet.
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be periodically reassessed for each individual patient based on potential benefits and risks, particularly after 5 or more years of use.

• Children: The safety and efficacy of the drug in pediatric patients have not been established.
• Elderly: There are no specific dosage recommendations for elderly patients. Clinical studies have included patients over 65 years of age, and no age-specific adverse events have been reported in this population.
• Patients with renal impairment: Clodronate is primarily eliminated via the kidneys. Therefore, it should be used with caution in patients with renal impairment. Dose reduction of clodronate is recommended as follows:

Clodronate is recommended to be administered before hemodialysis, with a 50% dose reduction on dialysis-free days, and the treatment regimen should be limited to 5 days. It should be noted that peritoneal dialysis poorly removes clodronate from the circulation.
The solution is incompatible with alkaline solutions or oxidizing solutions.