Clody

Package leaflet: Information for the patient

CLODY 100 mg+33 mg injection 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, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What CLODY is and what it is used for

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

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

2. What you should know before using CLODY

Do not use CLODY

• 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 CLODY.
• If you are allergic to lidocaine or to other amide-type local anesthetics, such as bupivacaine, mepivacaine, ropivacaine, or 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, sino-atrial, atrioventricular or intraventricular block).
• If you have weakened heart function unable to supply adequate blood flow to the body (acute heart failure).
• If you suffer from low blood volume (hypovolemia).
• This medicine is for intramuscular use only (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 serious adverse reactions due to high blood levels of the local anesthetic lidocaine (see section 3. If you use more CLODY than you should).

Warnings and precautions
Talk to your doctor or pharmacist before using CLODY.
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 CLODY).
In particular, inform your doctor if:

• You have high levels of calcium in your blood.
• You suffer from kidney disease (renal insufficiency).
• You are being treated with CLODY for cancer or osteoporosis and are undergoing dental treatment or need dental surgery. You should also inform your dentist that you are being treated with CLODY (see section 4. Possible side effects), as preventive dental treatment may be necessary.
• You suffer from heart diseases (particularly heart rhythm disorders with slow heart rate or heart failure) or have had heart surgery.
• You suffer from liver disease.
• 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).
• You experience thigh, hip or groin pain or weakness during treatment, as this may be an early symptom of a possible femoral fracture (see section 4. Possible side effects).
• You suffer from seizures (epilepsy). Your doctor will closely monitor you for any possible symptoms.
• You suffer from respiratory or pulmonary disorders.
• You suffer from a disease causing muscle weakness (myasthenia gravis).
• 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 CLODY
Inform your doctor or pharmacist if you are currently 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 CLODY with other bisphosphonates is contraindicated (see section 2. Do not use CLODY).
• 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 heartbeats, such as beta-blockers (e.g. propranolol), calcium channel blockers (e.g. amiodarone), or sodium channel blockers, as lidocaine may remain in the bloodstream longer.
• You are taking cimetidine, a medicine mainly used to treat gastritis and gastric ulcers (stomach wall lesions); fluvoxamine (a medicine used for depression); antiviral medicines such as ritonavir; macrolide antibiotics such as erythromycin or antibiotics like ciprofloxacin; antifungal medicines such as ketoconazole or itraconazole, as this may lead to increased blood levels of lidocaine.
• You are taking barbiturates such as phenobarbital; medicines used to treat epilepsy such as carbamazepine; phenytoin; primidone; oral contraceptives or hormone replacement therapy, as this may lead to decreased blood levels of lidocaine.
• You are being treated with digitalis, medicines used to treat heart rhythm disorders, as this may increase the risk of heart rhythm disturbances.
• 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, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before using this medicine.
Pregnancy
Avoid using CLODY 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, while lidocaine is excreted in breast milk in small amounts. Therefore, breastfeeding should be discontinued during treatment with CLODY.
Fertility
It is not known whether clodronic acid and lidocaine have effects on human fertility.

Driving and using machines
CLODY 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 CLODY than you should, avoid driving and operating machinery.

CLODY contains sodium
CLODY 100 mg+33 mg injectable solution with lidocaine contains less than 1 mmol (23 mg) of sodium per dose, i.e. essentially “sodium-free”.

3. How to use CLODY

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. If you have any doubts, consult your doctor or pharmacist (see the section DOSAGE, METHOD AND DURATION OF ADMINISTRATION at the end of this Package 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
CLODY 100 mg+33 mg injection solution with lidocaine is 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 CLODY than you should
If you accidentally take too much CLODY, 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 intravenously administered clodronic acid,
• high levels of nitrogen in the blood (uremia),
• liver damage,
• low levels of calcium in the blood (hypocalcemia).

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 (cardiovascular collapse).

Treatment
Your doctor will manage the symptoms with specific therapies.

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

If you stop using CLODY
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 develop vision or eye disturbances during treatment, STOP the treatment and consult an ophthalmologist.
Contact 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 tissue death in 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 according to 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 limits.

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),
• transaminase levels in the blood more than twice the upper normal limit, without other signs of liver dysfunction,
• allergic reactions manifesting as skin reactions,
• unusual femur fracture (the long bone of the leg), 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 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 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 adverse reaction 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 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 CLODY.

• 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 CLODY.
• pain or sores in the mouth or jaw and/or maxilla (two facial bones). These may be early signs of serious problems (jaw and/or maxilla bone tissue death), 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

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

Side effects specific to lidocaine
The following side effects are associated with lidocaine; however, insufficient data are available to determine the frequency of the individual events listed. Side effects are generally due to either allergic reactions or excessively high blood concentrations resulting from 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 reaction), 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 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
Slowed heart rate (bradycardia), irregular heart rhythms (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), skin eruption with itchy or non-itchy wheals (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 CLODY

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 no longer required. This will help protect the environment.

6. Package contents and other information

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

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

Description of the appearance of CLODY and pack contents
CLODY 100 mg+33 mg injectable solution with lidocaine
Clear, colourless injectable solution in packs of 6-12 vials for intramuscular use.
Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Promedica Srl – Via Palermo, 26/A – Parma
Manufacturer
CLODY 100 mg+33 mg injectable solution with lidocaine
Abiogen Pharma SpA – 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 and Primary hyperparathyroidism
The following dosage regimen is indicative and may therefore be adjusted according to the individual patient's needs.
a) Initial phase
CLODY 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 (serum calcium, hydroxyprolinuria, etc.).
For further information regarding CLODY 300 mg/10 ml concentrate for solution for infusion, please refer to the corresponding Summary of Product Characteristics and Package Leaflet.
b) Maintenance phase
CLODY 100 mg+33 mg injectable solution with lidocaine
100 mg once daily by intramuscular injection for 2-3 weeks.
Alternatively,
oral clodronate formulation may be considered.
CLODY is available only in formulations for intramuscular and intravenous infusion use. Therefore, for oral therapy, a medicinal product with an available oral formulation of clodronate must be prescribed.
The duration of treatment, usually long-term, depends on the progression of the disease. Periodic reassessment of bone resorption parameters is recommended to guide 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
CLODY 100 mg+33 mg injectable solution with lidocaine
100 mg by intramuscular injection every 7-14 days for one year or longer, depending on the patient's condition.
CLODY 200 mg+40 mg injectable solution with lidocaine
200 mg by intramuscular injection every 14-28 days for one year or longer, depending on the patient's condition.
CLODY 200 mg+40 mg injectable solution with lidocaine
may be used in patients who have never previously received clodronate treatment.
When switching from CLODY 100 mg+33 mg to CLODY 200 mg+40 mg, administration of one vial of CLODY 200 mg+40 mg every 14 days may be used as an alternative dosage regimen in patients already receiving one 100 mg vial weekly.
Administration of one vial of CLODY 200 mg+40 mg every 28 days may be used as an alternative dosage regimen in patients already receiving one 100 mg vial every two weeks.
Alternatively
Oral therapy
CLODY is available only in formulations for intramuscular and intravenous infusion use.
Therefore, for oral therapy, a medicinal product with an available oral formulation of clodronate must be prescribed.
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.

Special populations

• Children: The safety and efficacy of the drug in pediatric patients have not been established.
• Elderly: No specific dosage recommendations for the elderly. 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 removes clodronate poorly from the circulation.
The solution is incompatible with alkaline solutions or oxidising solutions.

Patient Information Leaflet

CLODY 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 may be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, consult your doctor or pharmacist. See section 4.

Contents of this leaflet:

1. What CLODY is and what it is used for
2. What you need to know before using CLODY
3. How to use CLODY
4. Possible side effects
5. How to store CLODY
6. Package contents and other information

1. What CLODY is and what it is used for

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

• bone weakening due to 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 weakening (osteoporosis) after the menopause (the period of permanent cessation of menstrual cycles).

2. What you need to know before using CLODY

Do not use CLODY

• 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 CLODY.
• If you are allergic to lidocaine or to other amide-type local anesthetics, such as for example: 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 have a condition of reduced blood volume (hypovolemia).
• This 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 the high blood concentration of the anesthetic lidocaine (see section 3. If you use more CLODY than you should).

Warnings and precautions

Talk to your doctor or pharmacist before using CLODY.

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 CLODY).

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 CLODY for cancer or osteoporosis and are undergoing dental treatment or are scheduled for dental surgery. Also inform your dentist that you are being treated with CLODY (see section 4. Possible side effects), as preventive dental treatment may be necessary.
• If you have heart diseases (particularly heart rhythm disorders with low heart rate and heart failure) or if you have undergone heart surgery.
• If you have a liver disease.
• If you, or someone in your family, suffer from a condition causing a marked increase in body temperature following the use of local anesthetics such as lidocaine (malignant familial hyperthermia).
• If during treatment you experience weakness or pain in the thigh, hip, or groin, as this could be an early symptom 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 possible 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 cell 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 CLODY

Tell 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 CLODY with other bisphosphonates is contraindicated (see section 2. Do not use CLODY).
• 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 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 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 of the stomach wall); fluvoxamine (a medicine used for depression); antiviral medicines such as ritonavir; macrolide antibiotics such as erythromycin or antibiotics like ciprofloxacin; antifungal medicines such as ketoconazole, itraconazole, as this may lead to increased blood levels of lidocaine.
• You are taking barbiturates such as phenobarbital; medicines used to treat epilepsy such as carbamazepine; phenytoin; primidone; oral contraceptives or hormone replacement therapy, as this may lead to decreased blood levels of lidocaine.
• You are being treated with digitalis, medicines used to treat heart rhythm disorders, as this may increase the risk of heart rhythm disturbances.
• 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, breast-feeding and fertility

If you are pregnant, think you may be pregnant, planning to become pregnant, or breast-feeding, consult your doctor or pharmacist before using this medicine.

Pregnancy

Avoid using CLODY 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, whereas lidocaine is excreted in breast milk in small amounts. Therefore, during treatment with CLODY, breastfeeding should be discontinued.

Fertility

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

Driving and using machines

CLODY 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 CLODY than you should, avoid driving and using machinery.

CLODY contains sodium

CLODY 200 mg+40 mg injectable solution with lidocaine contains 32.9 mg of sodium (the main component of table salt) per dose. This corresponds to 2% of the maximum recommended daily dietary intake for an adult.

3. How to use CLODY

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. 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 take an adequate amount of fluids.

Method of administration
CLODY 200 mg+40 mg injectable solution with lidocaine is 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 CLODY than you should
In case of accidental overdose, 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 intravenously administered clodronic acid,
• high levels of nitrogen in the blood (uraemia),
• liver damage,
• low levels of calcium in the blood (hypocalcaemia).

In case of accidental intravascular injection, symptoms of lidocaine overdose may occur, such as:

• 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 contraction of a muscle),
• uncontrolled body movements (convulsions),
• reduced blood flow to the body (cardio-circulatory collapse).

Treatment
Your doctor will manage the symptoms with specific therapies.

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

If you stop using CLODY
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 develop visual disturbances or eye problems during treatment, STOP the treatment and consult an ophthalmologist.
Immediately inform your doctor 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 tissue death in 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 levels of calcium in the blood, without symptoms (asymptomatic hypocalcemia),
• diarrhea, 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 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 fracture of the femur (long bone in the leg), 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 femoral 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 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);
• inflammation of the eye (episcleritis, scleritis, and uveitis). Episcleritis and scleritis have been reported with other drugs in the same class as clodronic acid (a class adverse reaction 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 concomitant use of diclofenac). See section 2. Other medicines and CLODY.

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 CLODY.
• 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 in 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 patients with cancer.

Effects related to the injection site

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

Side effects specific to lidocaine
Below are the side effects associated with lidocaine. There are insufficient data to determine the frequency of the individual effects listed. Side effects are generally due to either allergic reactions or excessively high blood concentrations resulting from 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
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 leading to tight closure of the jaw (trismus), altered sensation in limbs or other body parts (paresthesia).
Psychiatric disorders
Anxiety, disorientation.
Cardiac disorders
Slowing of the heart rate (bradycardia), changes in 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 (dyspnea), 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 wheals (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 CLODY

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 CLODY contains
CLODY 200 mg+40 mg injectable solution with lidocaine

• The active substances are Clodronic acid disodium salt (disodium clodronate) 200 mg and Lidocaine hydrochloride monohydrate 40 mg.
• Other components: Sodium bicarbonate (see section 2. CLODY contains sodium), water for injections.

Description of the appearance of CLODY and pack contents
CLODY 200 mg+40 mg injectable solution with lidocaine
Clear, colourless injectable solution, in packs of 3-6 vials for intramuscular use.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Promedica Srl – Via Palermo, 26/A – Parma
Manufacturer
CLODY 200 mg+40 mg injectable solution with lidocaine
Abiogen Pharma SpA – 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 and Primary hyperparathyroidism
The following dosage regimen is indicative and may therefore be adjusted according to the individual patient's needs.

c) Initial treatment phase
CLODY 300 mg/10 ml concentrate for solution for infusion: 300 mg once daily by slow intravenous infusion for 3-8 days, depending on clinical and laboratory parameters (serum calcium, hydroxyprolinuria, etc.).
For further information regarding CLODY 300 mg/10 ml concentrate for solution for infusion, refer to the corresponding Summary of Product Characteristics and Package Leaflet.

d) Maintenance phase
CLODY 100 mg+33 mg injectable solution with lidocaine:
100 mg daily by intramuscular injection for 2-3 weeks.

Alternatively,
consideration may be given to using an oral clodronate formulation.
CLODY is available only in formulations for intramuscular and intravenous infusion use. Therefore, for oral therapy, a medicinal product with an oral formulation of clodronate must be prescribed.

The duration of treatment, usually long-term, depends on the course 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
Dosage, based on clinical status and bone mineral density values, may vary as follows:

Parenteral therapy
CLODY 100 mg+33 mg injectable solution with lidocaine:
100 mg by intramuscular injection every 7-14 days for one year or longer, depending on the patient's condition.

CLODY 200 mg+40 mg injectable solution with lidocaine:
200 mg by intramuscular injection every 14-28 days for one year or longer, depending on the patient's condition.

CLODY 200 mg+40 mg injectable solution with lidocaine may be used in patients who have never previously received clodronate treatment.

When switching from CLODY 100 mg+33 mg to CLODY 200 mg+40 mg:
Administration of one vial of CLODY 200 mg+40 mg every 14 days may be used as an alternative dosing regimen in patients already receiving one 100 mg vial weekly.
Administration of one vial of CLODY 200 mg+40 mg every 28 days may be used as an alternative dosing regimen in patients already receiving one 100 mg vial every two weeks.

Alternatively:
Oral therapy
CLODY is available only in formulations for intramuscular and intravenous infusion use.
Therefore, for oral therapy, a medicinal product with an oral formulation of clodronate must be prescribed.

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 drug in paediatric patients have not been established.
• Elderly: No specific dosage recommendations are required for elderly patients. Clinical studies have included patients aged over 65 years, and no age-specific adverse events have been reported.
• Patients with renal impairment: Clodronate is primarily eliminated via the kidneys. Therefore, it must be used with caution in patients with renal impairment.

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

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

Patient information leaflet

CLODY 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, as it could be harmful.
• If you experience any side effect, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

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

1. What CLODY is and what it is used for

CLODY is a medicine containing clodronic acid, an active substance belonging to a group of drugs used to treat bone diseases, called bisphosphonates.
CLODY 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 need to know before using CLODY

Do not use CLODY

• 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 CLODY.

Warnings and precautions
Talk to your doctor or pharmacist before using CLODY.
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 CLODY).
In particular, inform your doctor:

• If you have high levels of calcium in your blood.
• If you have a kidney disease (renal insufficiency).
• If you are being treated with CLODY for cancer and are undergoing dental treatment or need a dental surgical procedure. You must also inform your dentist that you are being treated with CLODY (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 symptom of a possible femur fracture (see section 4. Possible side effects).

Children and adolescents
The safety and efficacy of the medicine in pediatric patients have not been established.
Other medicines and CLODY
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 CLODY with other bisphosphonates is contraindicated (see section 2. Do not use CLODY).
• 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, think you might be pregnant, planning to become pregnant, or breastfeeding,
ask your doctor or pharmacist for advice before being given this medicine.
Pregnancy
Avoid using CLODY during pregnancy and if you are of childbearing age and are not using an effective contraceptive method (medicines used to prevent pregnancy).
Breastfeeding
It is not known whether clodronic acid passes into breast milk. Therefore, during treatment with CLODY,
you should stop breastfeeding.
Fertility
It is not known whether clodronic acid has effects on human fertility.
Driving and using machines
CLODY may cause visual disturbances that may 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 CLODY than you should, avoid driving and using machinery.
CLODY contains sodium
This medicine contains 48.89 mg of sodium (the main component of table salt) per dose.
This corresponds to 2.46% of the maximum recommended daily dietary intake for an adult.

3. How to use CLODY

Use this medicine exactly as instructed 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 to you by a doctor or a 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 necessary to maintain adequate fluid intake.
This is particularly important when CLODY is administered intravenously:

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

Method of administration
CLODY 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 CLODY than you should
If you accidentally take an excessive dose of CLODY, 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 therapies.
If you forget to use CLODY
Do not take a double dose to make up for the missed dose.
If you stop using CLODY
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 gets them.
If you experience any visual disturbances or eye problems 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 listed below are categorized by frequency:
Common (may affect up to 1 in 10 people)

• decreased levels of calcium in the blood, without symptoms (asymptomatic hypocalcaemia),
• 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 hypocalcaemia),
• 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 liver function abnormalities,
• allergic reactions manifesting as skin reactions,
• unusual femur fracture (thigh bone), 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 determined from available data:
Effects related to the eyes

• inflammation of the conjunctiva, the membrane covering the eye and inner eyelids (conjunctivitis);
• inflammation of the eye (episcleritis, scleritis, and uveitis). Episcleritis and scleritis have been reported with other drugs in the same class as clodronic acid (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 breathing 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 CLODY.
  • 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 CLODY.
• 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 at 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, inform your doctor or pharmacist. You can also report side effects directly via the national reporting system at http://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 CLODY

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 CLODY 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. CLODY contains sodium), water for injections.

Description of the appearance of CLODY and contents of the pack
CLODY is a concentrate for infusion solution and is presented as a clear, colourless solution free from visible particles, in packs of 6–12 vials for intravenous use.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
PROMEDICA S.r.l. - Via Palermo 26/A - PARMA
Manufacturer
Abiogen Pharma S.p.A. - Via Meucci, 36 - Ospedaletto, PISA - Italy

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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 is indicative and may be adjusted according to the individual patient's needs.

a) Initial phase
CLODY 300 mg/10 ml concentrate for infusion solution, 300 mg once daily by slow intravenous infusion for 3–8 days, depending on clinical and laboratory parameters (serum calcium, hydroxyprolinuria, etc.).
Clodronate is administered as a slow intravenous infusion of 300 mg (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
CLODY 100 mg+33 mg injectable solution with lidocaine
100 mg daily by intramuscular injection for 2–3 weeks. For further information on CLODY 100 mg+33 mg injectable solution with lidocaine, refer to the corresponding Summary of Product Characteristics and Patient Leaflet.
Alternatively,
an oral clodronate formulation may be considered.
CLODY is available only in intramuscular and intravenous infusion formulations. Therefore, for oral therapy, a medicinal product containing an orally available clodronate formulation must be prescribed.

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: 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 renal route. Therefore, it must 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 dialysis-free 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).