Clasteon

Package leaflet: Information for the patient

CLASTEON 400 mg hard capsules

Clodronic acid
Read all of 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 others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What CLASTEON is and what it is used for

CLASTEON is a medicine containing clodronic acid, an active substance that belongs to a group of drugs used to treat bone diseases, known as bisphosphonates.
CLASTEON is used in adults for the treatment of:

• bone thinning caused by cancer (tumour-induced osteolysis);
• cancer of the bone marrow (multiple myeloma);
• overactivity of the parathyroid glands (primary hyperparathyroidism).

It is also used in women for the prevention and treatment of bone thinning (osteoporosis) after the menopause (the period of permanent cessation of menstrual cycles).

2. What you should know before taking CLASTEON

Do not take CLASTEON

• 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 CLASTEON.

Warnings and precautions
Talk to your doctor or pharmacist before taking CLASTEON.
Before and during treatment, your doctor will ask you to have 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 CLASTEON).
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 CLASTEON for cancer or osteoporosis and are undergoing dental treatment or need dental surgery. Also inform your dentist that you are being treated with CLASTEON (see section 4. Possible side effects), as you may require preventive dental care.

• 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 esophagus (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 advise you to carefully follow the administration instructions and to be alert for any signs or symptoms suggesting a possible esophageal reaction. If you develop symptoms of esophageal 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 pediatric patients have not been established.
Other medicines and CLASTEON
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 CLASTEON with other bisphosphonates is contraindicated (see section 2. Do not take CLASTEON).
• 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 concentrations of estramustine may increase.
• You are taking medicines containing bivalent cations (e.g., mineral supplements, antacids, or iron preparations). In such cases, your doctor will advise you to take CLASTEON at least 2–3 hours apart.

CLASTEON 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, aluminum, calcium) (see section 3. How to take CLASTEON).
CLASTEON must be taken at least 2–3 hours apart from foods and/or drinks containing bivalent cations.
Pregnancy, breast-feeding and fertility
If you are pregnant, think you might be pregnant, are planning to become pregnant, or are breast-feeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
Avoid taking CLASTEON during pregnancy and if you are of childbearing age and not using effective contraception (medicines used to prevent pregnancy).
Breast-feeding
It is not known whether clodronic acid passes into breast milk. Therefore, during treatment with CLASTEON, discontinue breast-feeding.
Fertility
It is not known whether clodronic acid has effects on human fertility.
Driving and using machines
CLASTEON 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 CLASTEON than you should, avoid driving and using machines.
CLASTEON contains sodium
CLASTEON 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 recommended dietary intake 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 CLASTEON

Take 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. If you have any doubts, consult your doctor or pharmacist (see the section DOSAGE, METHOD AND DURATION OF ADMINISTRATION at the end of the
Package Leaflet).
Clodronic acid is primarily eliminated via the kidneys. Therefore, during treatment with clodronic acid, you must ensure adequate fluid intake.

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

b) Maintenance phase
If your doctor prescribes CLASTEON capsules, the recommended dose is 4 capsules daily, taken as a single administration. If your doctor prescribes a higher dose, up to a maximum of 8 capsules per day, the dose exceeding 4 capsules should be taken separately (as a second dose). The doses must be taken 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 CLASTEON 100 mg + 33 mg injectable solution with lidocaine into a muscle at a dose of 100 mg/day for 2–3 weeks, according to the instructions described in the corresponding Package Leaflet.

Your doctor will reduce your dose of CLASTEON 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 break (repeated in cycles), or 1 capsule daily continuously for 1 year or longer, depending on your doctor’s prescription.

Alternatively, your doctor may administer CLASTEON 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 described in the corresponding Package Leaflet, or CLASTEON 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 described in the corresponding Package Leaflet.

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

How to take the capsules
Take the capsules orally with some water and swallow without chewing.
CLASTEON 400 mg capsules must be swallowed whole, preferably in the morning, on an empty stomach, with a glass of water. After taking the capsule, do not eat, drink, or take any other oral medicines for one hour. 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 required, 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 CLASTEON 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 clodronic acid administered intravenously),
• elevated blood nitrogen levels (uremia),
• liver damage,
• low blood calcium levels (hypocalcemia).
  Treatment: Your doctor will monitor symptoms and provide specific therapies.

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

If you stop taking CLASTEON
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 disturbances or eye problems 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), usually 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 levels of calcium in the blood, without symptoms (asymptomatic hypocalcemia),
• diarrhoea, nausea, vomiting (usually mild in intensity),
• increased levels of transaminases in the blood (a test to assess liver function), usually within normal limits.

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

• decreased levels of calcium in the blood, with symptoms (symptomatic hypocalcemia),
• increased levels of parathyroid hormone (a hormone that regulates calcium levels in the blood) associated with reduced calcium in the blood,
• increased levels of alkaline phosphatase in the blood (a test to assess bone and liver condition),
• increased levels of transaminases 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 bone of the leg), particularly in patients on 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 episodes 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 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 (acetylsalicylic acid);
  • 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 concomitant use of diclofenac). See section 2. Other medicines and CLASTEON.

• 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 CLASTEON;
  • 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 occurred in patients with cancer.

• 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);
  • lesions of the stomach and intestine (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 CLASTEON

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 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 CLASTEON 400 mg hard capsules contains

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

Description of the appearance of CLASTEON and pack contents
CLASTEON 400 mg hard capsules are supplied in blisters of 10 capsules.
Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
ABIOGEN PHARMA S.p.A. - Via Meucci 36 – Loc. Ospedaletto - Pisa
Manufacturer
ABIOGEN PHARMA S.p.A. - Via Meucci 36 – Loc. Ospedaletto - Pisa

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The following information is intended exclusively for physicians or healthcare professionals:
DOSAGE, METHOD AND TIME OF ADMINISTRATION
Tumoral 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
CLASTEON 300 mg/10 ml concentrate for solution for infusion, 300 mg once daily by slow intravenous infusion for 3–8 days, depending on the clinical and laboratory parameters (calcemia, hydroxyprolinuria, etc.).
For further information regarding CLASTEON 300 mg/10 ml concentrate for solution for infusion, please refer to the corresponding Summary of Product Characteristics and Package Leaflet.
b) Maintenance phase
CLASTEON 100 mg + 33 mg injectable solution with lidocaine
100 mg daily by intramuscular injection for 2–3 weeks. For further information regarding CLASTEON 100 mg + 33 mg injectable solution with lidocaine, please refer to the corresponding Summary of Product Characteristics and Package Leaflet.
or alternatively
CLASTEON 400 mg hard capsules, 4 capsules/day (1600 mg of clodronate sodium). If necessary, the dose may be increased, but must not exceed a maximum of 8 capsules/day (3200 mg of clodronate sodium). 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 should be administered apart from meals.
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.

Prevention and treatment of postmenopausal osteoporosis.
The dosage, depending on the clinical condition and bone mineral density values, may vary as follows:
Oral therapy
CLASTEON 400 mg hard capsules, 1 capsule/day for 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.
Parenteral therapy
CLASTEON 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.
CLASTEON 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.
For further information regarding CLASTEON 100 mg + 33 mg injectable solution with lidocaine and CLASTEON 200 mg + 40 mg injectable solution with lidocaine, please refer to 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 years or more of use.

Method of administration
CLASTEON 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 content and therefore should not be used.
Exclusively for the treatment of tumoral osteolysis, multiple myeloma, and primary hyperparathyroidism, in case of multiple daily doses, the second 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.

Special populations

• 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.
• Patients with renal impairment: Clodronate is primarily eliminated via the renal route. Therefore, it should 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:

* For oral clodronate, pharmacokinetic data are not available in patients with renal insufficiency and creatinine clearance below 10 ml/min. Use in these cases should be avoided, except for short-term treatments in the presence of purely functional renal insufficiency caused by high serum calcium levels.

Patient Information Leaflet

CLASTEON 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 effect, including those not listed in this leaflet, talk to your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

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

1. What CLASTEON is and what it is used for

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

• of bone weakening caused by cancer (tumour-induced osteolysis);
• of multiple myeloma (a cancer of the bone marrow);
• of overactive parathyroid glands (primary hyperparathyroidism).

2. What you should know before using CLASTEON

Do not use CLASTEON

• 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 CLASTEON.

Warnings and precautions
Talk to your doctor or pharmacist before using CLASTEON.
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 CLASTEON).
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 CLASTEON 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 CLASTEON (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 femur 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 CLASTEON
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 CLASTEON with other bisphosphonates is contraindicated (see section 2. Do not use CLASTEON).
• 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 concentrations 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, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before being administered this medicine.
Pregnancy
Avoid using CLASTEON during pregnancy and if you are of childbearing age and not using an effective contraceptive method (medicines used to prevent pregnancy).
Breast-feeding
It is not known whether clodronic acid passes into breast milk. Therefore, discontinue breast-feeding during treatment with CLASTEON.
Fertility
It is not known whether clodronic acid has effects on human fertility.
Driving and using machines
CLASTEON 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 CLASTEON than you should, avoid driving and operating machinery.
CLASTEON contains sodium
This medicine contains 48.89 mg of sodium (a key component of table salt) per dose. This corresponds to 2.46% of the maximum daily dietary intake recommended 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 CLASTEON

Use 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. This medicine will be administered by a doctor or nurse (see the section DOSAGE, METHOD AND DURATION OF ADMINISTRATION at the end of the Package Leaflet).

Clodronic acid is primarily eliminated via the kidneys. Therefore, during treatment with clodronic acid, it is essential that you drink an adequate amount of fluids.
This is particularly important when CLASTEON is administered intravenously:

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

Method of administration
CLASTEON 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 CLASTEON 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 calcium levels in the blood (hypocalcemia).

Treatment
Your doctor will manage symptoms with appropriate specific therapies.

If you forget to use CLASTEON
Do not take a double dose to make up for the missed dose.

If you stop treatment with CLASTEON
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 eye or vision disturbances during treatment, STOP the treatment 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 death 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 are listed below 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 blood transaminase levels (a test to assess liver function), usually within normal limits.

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

• decreased blood calcium levels with symptoms (symptomatic hypocalcemia),
• 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 blood transaminase levels (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 osteoporosis treatment. Contact your doctor if you experience pain or weakness in the thigh, hip, or groin, as this may 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 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 medicines belonging to the same class as clodronic acid (a class effect of bisphosphonates).

• effects related to the lungs

• breathing problems in patients with aspirin-sensitive asthma (a medicine used to treat fever, pain, and inflammation);

• allergic reactions manifesting as respiratory disorders.

• effects related to the kidneys and urinary tract

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

• 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 CLASTEON;

• pain or sores in the mouth or jaw and/or maxilla (two facial bones). These may be early signs of serious problems (bone death 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 occurred in patients with cancer.

• effects related to the injection site

• pain at the injection site, possibly related to 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 CLASTEON

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 use this medicine if you notice that the solution is opalescent and/or contains visible particles, or if the solution is yellow or yellowish-brown.
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 CLASTEON 300 mg/10 ml concentrate for infusion solution contains

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

Description of the appearance of CLASTEON and package contents
CLASTEON 300 mg/10 ml concentrate for infusion solution
CLASTEON is a concentrate for infusion solution supplied in packs of 6–12 vials for intravenous use.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
ABIOGEN PHARMA S.p.A. - Via Meucci 36 – Loc. Ospedaletto - Pisa
Manufacturer
ABIOGEN PHARMA S.p.A. - Via Meucci 36 – Loc. Ospedaletto - Pisa

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The following information is intended exclusively for physicians or healthcare professionals:
This medicinal product is for intravenous use only.
Must be diluted before administration.
The solution is incompatible with alkaline solutions or oxidizing solutions.

DOSAGE, METHOD AND DURATION OF ADMINISTRATION
Tumor-induced 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
CLASTEON 300 mg/10 ml concentrate for infusion solution, 300 mg once daily by slow intravenous infusion for 3–8 days, depending on the clinical and laboratory parameters (serum calcium, hydroxyprolinuria, etc.).
Clodronate is administered as a 300 mg intravenous infusion (one 10 ml vial per day) diluted in 500 ml of 0.9% sodium chloride solution (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
CLASTEON 100 mg + 33 mg injectable solution with lidocaine
100 mg daily by intramuscular injection for 2–3 weeks. For further information on CLASTEON 100 mg + 33 mg injectable solution with lidocaine, refer to the corresponding Summary of Product Characteristics and Patient Leaflet.
Alternatively,
CLASTEON 400 mg hard capsules, 4 capsules daily (1600 mg of sodium clodronate). If necessary, the dose may be increased, but must not exceed a maximum of 8 capsules daily (3200 mg of sodium clodronate).
For further information on CLASTEON 400 mg hard capsules, refer to the corresponding Summary of Product Characteristics and Patient 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 pediatric patients have not been established.
• Elderly: No specific dosage recommendations are required for elderly patients. Clinical studies have included patients over 65 years of age, and no age-specific adverse events have been reported.
• 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 haemodialysis, to reduce the dose by 50% on dialysis-free days, and to limit the treatment schedule to 5 days. It should be noted that peritoneal dialysis poorly removes clodronate 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).

Package leaflet: information for the patient

CLASTEON 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 other people, even if their symptoms are the same as yours, as it could 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 CLASTEON is and what it is used for
2. What you need to know before using CLASTEON
3. How to use CLASTEON
4. Possible side effects
5. How to store CLASTEON
6. Package contents and other information

1. What CLASTEON is and what it is used for

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

• of bone weakening due to tumour (tumour-induced osteolysis);
• of bone marrow tumour (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 menstrual cessation).

2. What you should know before using CLASTEON

Do not use CLASTEON

• 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 CLASTEON.
• 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 a weak heart unable to supply sufficient blood to the body (acute heart failure).
• If you suffer from low blood volume (hypovolemia).

The medicine is for intramuscular use only (i.e. to be injected into a muscle) and must not be
administered into a blood vessel (intravenously). Accidental injection into a vein increases the risk of severe adverse reactions due to high blood levels of the local anesthetic lidocaine (see section 3. If you use more CLASTEON than you should).

Warnings and precautions

Talk to your doctor or pharmacist before using CLASTEON.

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 CLASTEON).

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 CLASTEON for cancer or osteoporosis and are undergoing dental treatment or are scheduled for dental surgery. You should also inform your dentist that you are receiving CLASTEON treatment (see section 4. Possible side effects), as preventive dental care may be necessary.
• If you suffer from heart diseases (particularly rhythm disorders with slow heart rate and heart failure) or have had heart surgery.
• If you suffer from liver disease.
• If you or someone in your family suffers from a condition causing a marked increase in body temperature following the use of local anesthetics such as lidocaine (familial malignant hyperthermia).
• If during treatment you experience weakness or pain in the thigh, hip or groin, as this may be an early sign of a possible femur fracture (see section 4. Possible side effects).
• If you suffer from seizures (epilepsy). Your doctor will closely monitor you for any symptoms.
• If you suffer from respiratory or pulmonary disorders.
• If you suffer from 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 the medicine in pediatric patients have not been established.

Other medicines and CLASTEON

Tell 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 CLASTEON with other bisphosphonates is contraindicated (see section 2. Do not use CLASTEON).
• 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 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 conditions 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 of 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 medicines used to relax muscles 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, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine.

Pregnancy

Avoid using CLASTEON 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 CLASTEON, breastfeeding should be discontinued.

Fertility

It is not known whether clodronic acid and lidocaine have effects on human fertility.

Driving and using machines

CLASTEON 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 use more CLASTEON than you should, avoid driving and operating machinery.

CLASTEON contains sodium

CLASTEON 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'.

CLASTEON 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 recommended daily dietary intake for an adult.

This should be taken into account if you suffer from kidney disease or are on a low-sodium diet.

3. How to use CLASTEON

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 Leaflet).
Clodronic acid is primarily eliminated via the kidneys. Therefore, during treatment with clodronic acid, you must ensure adequate fluid intake.

Method of administration
CLASTEON 100 mg + 33 mg injectable solution with lidocaine and CLASTEON 200 mg + 40 mg injectable 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.
Avoid massaging the injection site.

If you use more CLASTEON than you should
If you accidentally take too much CLASTEON, 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 lidocaine overdose symptoms may occur:
• drowsiness,
• euphoria (state of excessive excitement),
• sedation (physical and mental relaxation),
• loss of sensation in parts of the body (paraesthesiae),
• muscle spasms (sudden, involuntary muscle contractions),
• uncontrolled body movements (convulsions),
• reduced blood flow to the body (cardiovascular collapse).

Treatment
The doctor will manage symptoms with appropriate specific therapies.

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

If you stop using CLASTEON
If you have any questions 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 eye or vision problems during treatment, STOP taking the medicine 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 death 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)

• decrease in blood calcium levels without symptoms (asymptomatic hypocalcemia),
• diarrhoea, nausea, vomiting (usually mild in intensity),
• increased levels of transaminases 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 hypocalcemia),
• increased levels of parathyroid hormone (a hormone regulating calcium levels) in the blood, associated with low blood calcium,
• increased levels of alkaline phosphatase in the blood (a test to assess bone and liver condition),
• increased levels of transaminases in the blood (a test to assess liver function) more than twice the upper normal limit, without other abnormalities in liver function,
• allergic reactions manifesting as skin reactions,
• unusual femur fracture (thigh bone), particularly in patients on 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 inner 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 problems in patients with aspirin-sensitive asthma (a medicine used to treat fever, pain, and inflammation);
• allergic reactions manifesting as respiratory disorders.
• Effects related to the kidneys and urinary tract
• kidney disease (renal failure), severe kidney damage. Rarely, and especially in association with 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 CLASTEON.
• 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 CLASTEON;
• pain or sores in the mouth or jaw and/or maxilla (two facial bones). These may be early signs of serious problems (bone tissue death 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.

Side effects specific to lidocaine
The following side effects are associated with lidocaine; insufficient data are available to determine the frequency of the individual effects listed. Side effects are generally due to either allergic reactions or excessively high blood concentrations caused by accidental intravascular injection and/or overdose. This may occasionally lead to central nervous system excitation and occasional cardiovascular depressive effects (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
Symptoms of excitation or depression associated with dizziness, drowsiness, visual disturbances, tremors, followed by changes in consciousness, seizures, coma, prolonged contraction of the jaw muscles causing tight closure of the jaw and maxilla (trismus), altered sensation in limbs or other body parts (paraesthesia).

Psychiatric disorders
Anxiety, disorientation.

Cardiac disorders
Slowed heart rate (bradycardia), irregular heart rhythm (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 reddening of the skin (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 weak 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 CLASTEON

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 pack 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 CLASTEON contains

• CLASTEON 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. CLASTEON contains sodium), water for injections.

CLASTEON 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. CLASTEON contains sodium), water for injections.

Description of the appearance of CLASTEON and contents of the pack
CLASTEON 100 mg + 33 mg injectable solution with lidocaine
Injectable solution in packs of 6-12 vials for intramuscular use.
CLASTEON 200 mg + 40 mg injectable solution with lidocaine
Injectable solution in packs of 3-6 vials for intramuscular use.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
ABIOGEN PHARMA S.p.A. - Via Meucci 36 – Loc. Ospedaletto - Pisa
Manufacturer
ABIOGEN PHARMA S.p.A. - Via Meucci 36 – Loc. 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 should be considered indicative and may therefore be adapted according to the individual patient's needs.
a) Initial phase
CLASTEON 300 mg/10 ml concentrate for infusion solution
300 mg/day as a single slow intravenous infusion for 3-8 days, depending on clinical and laboratory parameters (serum calcium, hydroxyprolinuria, etc.).
For further information on CLASTEON 300 mg/10 ml concentrate for infusion solution, please refer to the corresponding Summary of Product Characteristics and Package Leaflet.
b) Maintenance phase
CLASTEON 100 mg + 33 mg injectable solution with lidocaine
100 mg/day intramuscularly for 2-3 weeks
or alternatively,
CLASTEON 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 CLASTEON 400 mg hard capsules, please 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 re-evaluation of bone resorption parameters is recommended as a guide to assess the need for continuing therapy.

Prevention and treatment of postmenopausal osteoporosis.
The dosage, depending on the clinical condition and bone mineral density values, may vary as follows:
Parenteral therapy
CLASTEON 100 mg + 33 mg injectable solution with lidocaine
Intramuscular administration: 100 mg every 7-14 days, for 1 year or longer depending on the patient's condition.
CLASTEON 200 mg + 40 mg injectable solution with lidocaine
Intramuscular administration: 200 mg every 14-28 days, for 1 year or longer depending on the patient's condition.
CLASTEON 200 mg + 40 mg injectable solution with lidocaine can be used in patients who have never previously received clodronate treatment.
When switching from CLASTEON 100 mg + 33 mg to CLASTEON 200 mg + 40 mg, administration of one vial of CLASTEON 200 mg + 40 mg every 14 days may be used as an alternative dosage regimen in patients already receiving one vial of 100 mg weekly.
Administration of one vial of CLASTEON 200 mg + 40 mg every 28 days may be used as an alternative dosage regimen in patients already receiving one vial of 100 mg every two weeks.
Oral therapy
CLASTEON 400 mg hard capsules: 1 capsule/day for 30 days, followed by a 60-day treatment interruption (for multiple cycles), up to continuous administration of 1 capsule/day for 1 year or longer depending on the patient's condition.
For further information on CLASTEON 400 mg hard capsules, please refer to 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.

Special populations

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

It is recommended to administer clodronate before haemodialysis, to reduce the dose by 50% on dialysis-free days, and to limit the treatment regimen 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.