Niklod

Patient Information Leaflet

NIKLOD 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 effects, including those not listed in this leaflet, please inform your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What NIKLOD is and what it is used for

NIKLOD is a medicine containing clodronic acid, which belongs to a group of medicines used to treat bone diseases, called bisphosphonates.
NIKLOD is used in adults to treat:

• 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 should know before using NIKLOD

Do not use NIKLOD

• 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 NIKLOD.
• If you are allergic to lidocaine or to other amide-type local anesthetics, such as: bupivacaine, mepivacaine, ropivacaine, levobupivacaine.
• If you suffer from 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 acute heart failure, meaning a weakened heart unable to supply adequate blood to the body.
• 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 severe adverse reactions due to high blood levels of the anesthetic lidocaine (see section 3. If you use more NIKLOD than you should).

Warnings and precautions
Talk to your doctor or pharmacist before using NIKLOD.
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 liver or kidney problems (see section 3. How to use NIKLOD).

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 NIKLOD for cancer or osteoporosis and are undergoing dental treatment or are scheduled for dental surgery. You should also inform your dentist that you are being treated with NIKLOD (see section 4. Possible side effects), as preventive dental care may be necessary.
• If you suffer from heart diseases (especially heart rhythm disorders with slow heart rate and heart failure) or have had heart surgery.
• If you suffer from severe liver disease.
• If you or a family member suffer from a condition causing a marked increase in body temperature following the use of local anesthetics such as lidocaine (malignant familial hyperthermia).
• If you experience thigh, hip or groin pain or weakness during treatment, as this may be an early sign of a possible femoral 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 suffer from respiratory or lung 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 this medicine in pediatric patients have not been established.

Other medicines and NIKLOD
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 NIKLOD with other bisphosphonates is contraindicated (see section 2. Do not use NIKLOD).
• You are taking non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to treat inflammation (especially diclofenac), as kidney problems may occur.
• You are taking aminoglycosides, medicines used to treat infections, as blood calcium levels may decrease (hypocalcemia).
• You are taking estramustine, a medicine used to treat prostate cancer (a gland in men that produces seminal fluid), as blood levels of estramustine may increase.
• You are taking medicines used to treat heart disorders, including irregular heartbeat, such as beta-blockers (e.g. propranolol), calcium channel blockers (e.g. amiodarone), or sodium channel blockers, as lidocaine may remain in the bloodstream 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 such as 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, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before using this medicine.

Pregnancy
Avoid using NIKLOD during pregnancy or 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, during treatment with NIKLOD, breastfeeding should be discontinued.

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

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

Important information about certain excipients
NIKLOD contains sodium
NIKLOD 100 mg + 33 mg injectable solution with lidocaine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially 'sodium-free'.
NIKLOD 200 mg + 40 mg injectable solution with lidocaine contains 32.9 mg of sodium (main component of table salt) per dose. This corresponds to 1.6% of the maximum daily recommended dietary intake for an adult.

3. How to use NIKLOD

Use this medicine exactly as instructed 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 Package Leaflet).
Clodronic acid is primarily eliminated via the kidneys. Therefore, adequate fluid intake must be maintained during treatment with clodronic acid.
Method of administration
NIKLOD 100 mg + 33 mg injection solution with lidocaine and NIKLOD 200 mg + 40 mg injection solution with lidocaine are for intramuscular use only (i.e., to be injected into a muscle). To avoid accidental intravascular injection, it is recommended to aspirate before injecting the medicine.
Do not massage the injection site.
If you use more NIKLOD 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 clodronic acid administered intravenously),
• elevated blood nitrogen levels (uraemia),
• liver damage,
• low blood calcium levels (hypocalcaemia).

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

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

Treatment
The doctor will manage symptoms with appropriate specific therapies.
If you forget to use NIKLOD
Do not use a double dose to make up for the forgotten dose.
If you stop using NIKLOD
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 eye or vision problems during treatment, STOP taking the medicine 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 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)

• decrease in blood calcium levels without symptoms (asymptomatic hypocalcaemia),
• 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)

• decrease in blood calcium levels with symptoms (symptomatic hypocalcaemia),
• increased parathyroid hormone levels (a hormone regulating blood calcium levels) associated with low blood calcium,
• increased blood alkaline phosphatase levels (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 (thigh bone), particularly in patients receiving long-term treatment for osteoporosis. Contact your doctor if you experience pain or weakness in the thigh, hip, or groin, as this could be an early sign of a possible femur fracture.

Very rare (may affect up to 1 in 10,000 people)
Contact your doctor if you experience ear pain, ear discharge, and/or ear infection. These symptoms could indicate 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 (bisphosphonates)
• Effects related to the lungs
  • breathing difficulties in patients with aspirin-sensitive asthma (a medicine used to treat fever, pain, and inflammation);
  • allergic reactions manifesting as respiratory problems.
• Effects related to the kidneys and urinary tract
  • kidney disease (renal failure), severe kidney damage. Rarely, and especially in association with 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 NIKLOD.
• Effects related to bones and muscles
  • severe bone, joint, and muscle pain. Symptoms may appear from days to several months after starting treatment with NIKLOD.
  • 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 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 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), laryngeal swelling 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 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 skin redness (various types of skin rashes), itchy skin rash with raised bumps (urticaria), itching.
Ear and labyrinth disorders
Ringing in the ears (tinnitus), increased sensitivity to relatively soft 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 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 NIKLOD

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

6. Package Contents and Other Information

What NIKLOD Contains
NIKLOD 100 mg + 33 mg injectable solution with lidocaine

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

NIKLOD 200 mg + 40 mg injectable solution with lidocaine

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

Description of the Appearance of NIKLOD and Contents of the Package
NIKLOD 100 mg + 33 mg injectable solution with lidocaine
Injectable solution in packs of 6 vials for intramuscular use.
NIKLOD 200 mg + 40 mg injectable solution with lidocaine
Injectable solution in packs of 1, 3, 5, or 6 vials for intramuscular use.

Marketing Authorization Holder and Manufacturer
MARKETING AUTHORIZATION HOLDER
I.B.N. Savio S.r.l., Via del Mare, 36 00071 Pomezia (RM)

MANUFACTURER
NIKLOD 100 mg + 33 mg injectable solution with lidocaine
Savio Industrial S.r.l., Via E. Bazzano n° 14 – Ronco Scrivia (GE)
Abiogen Pharma SpA – Via Meucci, 36 – Loc. Ospedaletto – PISA

NIKLOD 200 mg + 40 mg injectable solution with lidocaine
Savio Industrial S.r.l., Via E. Bazzano n° 14 – Ronco Scrivia (GE)
Biomedica Foscama Industria Chimico-Farmaceutica S.p.A., Via Morolense 87, Ferentino – Italy

The responsible manufacturing site for release of the medicinal product will be indicated in each Package Leaflet.

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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 should be considered indicative and may therefore be adjusted according to the individual patient's needs.

a) Initial Phase
NIKLOD 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 on NIKLOD 300 mg/10 ml concentrate for solution for infusion, refer to the corresponding Summary of Product Characteristics and Package Leaflet.

b) Maintenance Phase
NIKLOD 100 mg + 33 mg injectable solution with lidocaine
100 mg daily by intramuscular injection for 2–3 weeks
or, alternatively,
a clodronate formulation for oral use may be considered. NIKLOD 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 as a guide to determine the need for continuing therapy.

Prevention and Treatment of Postmenopausal Osteoporosis
Dosage may vary according to clinical condition and bone mineral density values as follows.

Parenteral Therapy
NIKLOD 100 mg + 33 mg injectable solution with lidocaine
100 mg by intramuscular injection every 7–14 days, for 1 year or longer depending on the patient's condition.

NIKLOD 200 mg + 40 mg injectable solution with lidocaine
200 mg by intramuscular injection every 14–28 days, for 1 year or longer depending on the patient's condition.

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

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

Alternatively
Oral Therapy
NIKLOD 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.

Duration
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 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.
• Renal Impairment Clodronate is primarily eliminated via the renal route. Therefore, it must be used with caution in patients with renal impairment.

Parenteral Administration:
Dosage reduction of clodronate is recommended 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 removes clodronate poorly from the circulation.
Instructions for use
NIKLOD 100 mg + 33 mg injection solution with lidocaine and NIKLOD 200 mg + 40 mg injection solution with lidocaine are for intramuscular use only. To avoid accidental intravascular injection, it is recommended to aspirate before injecting the medicinal product.
Avoid massaging the injection site.
The solution is incompatible with alkaline solutions or oxidizing solutions.
For further information regarding NIKLOD 300 mg/10 ml concentrate for infusion solution, see the corresponding Summary of Product Characteristics and Patient Information Leaflet.

Patient information leaflet

NIKLOD 300 mg/10 ml concentrate for solution for infusion

Clodronic acid
Please read this leaflet carefully before you are given 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 NIKLOD is and what it is used for
2. What you need to know before you are given NIKLOD
3. How to use NIKLOD
4. Possible side effects
5. How to store NIKLOD
6. Contents of the pack and other information

1. What NIKLOD is and what it is used for

NIKLOD is a medicine containing clodronic acid, an active substance belonging to a group of medicines used to treat bone diseases called bisphosphonates.
NIKLOD is used in adults to treat:

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

2. What you need to know before using NIKLOD

Do not use NIKLOD

• 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 NIKLOD.

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

• You have high levels of calcium in your blood.
• You suffer from kidney disease (renal failure).
• You are being treated with NIKLOD 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 NIKLOD (see section 4. Possible side effects), as preventive dental treatment may be necessary.
• You suffer from liver disease.
• 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 NIKLOD
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
This is particularly important if:
Concomitant use with other bisphosphonates, medicines used to treat bone diseases, is contraindicated (see section 2. Do not use NIKLOD).
Be cautious and inform your doctor if:

• You are taking other bisphosphonates, medicines used to treat bone diseases, as concomitant use of NIKLOD with other bisphosphonates is contraindicated (see section 2. Do not use NIKLOD).
• 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 levels of calcium 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 a pregnancy, or breastfeeding, consult your doctor or pharmacist before this medicine is administered.
Pregnancy
Avoid using NIKLOD during pregnancy and if you are of childbearing age and not using an effective contraceptive method (medicines used to prevent pregnancy).
Breastfeeding
It is not known whether clodronic acid passes into breast milk. Therefore, discontinue breastfeeding during treatment with NIKLOD.
Fertility
It is not known whether clodronic acid has effects on human fertility.

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

NIKLOD contains sodium
This medicine contains 49.1 mg of sodium (the main component of table salt) per dose. This corresponds to 2.46% of the maximum daily recommended dietary intake for an adult.
This should be taken into consideration if you have kidney disease or are on a low-sodium diet.

The following information is intended exclusively for doctors or healthcare professionals:
Clodronate is administered as an 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 in 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
NIKLOD 100 mg + 33 mg injectable solution with lidocaine
100 mg daily by intramuscular injection for 2–3 weeks.

3. How to use NIKLOD

Use this medicine exactly as instructed by your doctor, who will determine the correct dose according to the severity of your condition and the duration of treatment. This medicine will be administered to you by a doctor or a nurse (see 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, it is necessary to maintain adequate fluid intake. This is particularly important when NIKLOD is administered intravenously:

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

Method of administration
NIKLOD 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 (over 2–3 hours) directly into a vein.
If you use more NIKLOD than you should
In case of accidental overdose, contact your doctor or go immediately to the nearest hospital.
Symptoms of overdose may include:

• increased creatinine levels in the blood, 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 symptoms with appropriate therapies.
If you forget to use NIKLOD
Do not take a double dose to make up for the missed dose.
If you stop treatment with NIKLOD
If you have any doubts about using this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine may cause side effects, although not everybody gets them.
If you experience any vision or eye 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 necrosis of the jaw and/or maxilla), usually associated with tooth extraction and/or local infection (see section 2. Warnings and precautions).

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

• decrease in blood calcium levels without symptoms (asymptomatic hypocalcemia)
• diarrhoea, nausea, vomiting (usually mild)
• increased transaminase levels in 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 parathyroid hormone levels (a hormone regulating blood calcium levels) associated with low blood calcium
• increased alkaline phosphatase levels in blood (a test to assess bone and liver condition)
• increased transaminase levels in 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
• atypical femur fracture (long bone of the leg), particularly in patients undergoing 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 signs of bone damage in the ear.

The following side effects may also occur, for which frequency cannot be estimated from the 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, uveitis). Episcleritis and scleritis have been reported with other drugs in the same class as clodronic acid (bisphosphonates)
• Effects related to the lungs
  • breathing difficulties in patients with aspirin-sensitive asthma (aspirin is 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 diclofenac). See section 2. Other medicines and NIKLOD.
• 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 NIKLOD
  • pain or sores in the mouth or jaw and/or maxilla (two facial bones). These may be early signs of serious problems (bone necrosis of the jaw and/or maxilla), usually associated with tooth extraction and/or local infection (see section 2. Warnings and precautions). In most cases, this has occurred in cancer patients.
• Effects related to the injection site
  • pain at the injection site, particularly with prolonged 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 may 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 NIKLOD

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

6. Package contents and other information

What NIKLOD 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. NIKLOD contains sodium), water for injections.

Description of the appearance of NIKLOD and package contents
NIKLOD is a concentrate for infusion solution, supplied in packs of 6 vials for intravenous use.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
I.B.N. Savio S.r.l., Via del Mare, 36 – 00071 Pomezia (RM)
Manufacturer
Savio Industrial S.r.l., Via E. Bazzano n° 14 – Ronco Scrivia (GE)

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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 should be considered indicative and may therefore be adjusted according to the individual patient's needs.

a) Initial treatment phase
NIKLOD 300 mg/10 ml concentrate for infusion solution, 300 mg/day as a single intravenous infusion for 3–8 days, depending on the course of clinical and laboratory parameters (serum calcium, hydroxyprolinuria, etc.).

Clodronate is administered as a 300 mg (one 10 ml vial)/day intravenous infusion, 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
NIKLOD 100 mg + 33 mg injectable solution with lidocaine
100 mg/day by intramuscular injection for 2–3 weeks.

These treatment cycles may be repeated at variable intervals depending on the disease progression. Periodic assessment of bone resorption parameters may be helpful in guiding treatment cycles.

For further information regarding NIKLOD 100 mg + 33 mg injectable solution with lidocaine, refer to the corresponding Summary of Product Characteristics and Package Leaflet.

Alternatively, an oral clodronate formulation may be considered.
NIKLOD is available only in intramuscular and intravenous infusion formulations. Therefore, for oral therapy, a medicinal product with an available oral clodronate formulation must be prescribed.

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 determine the need for continuing therapy.

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 aged over 65 years, and no age-specific adverse events have been reported in this age group.

• Patients with renal impairment
  Clodronate is primarily eliminated via the kidneys. Therefore, it should be used with caution in patients with renal impairment.

Parenteral administration
It is recommended to reduce the clodronate infusion dose 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. 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).