NIKLOD 100 mg/33 mg Injectable Solution

Зміст інструкції

1. NIKLOD 100 mg + 33 mg injectable solution with lidocaine, 200 mg + 40 mg injectable solution with lidocaine
   1. What is NIKLOD and what is it 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
2. NIKLOD 300 mg/10 ml concentrate for solution for infusion
   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

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

Clodronic acid - Lidocaine
Read this leaflet carefully before using this medicine as 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 pass it on to others, even if they have the same symptoms as you, as it could be harmful.
• If you get any side effects, even those not listed in this leaflet, tell 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 use 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 is NIKLOD and what is it used for

NIKLOD is a medicine that contains clodronic acid, which belongs to a group of medicines for the
treatment of bone diseases, called bisphosphonates.
NIKLOD is used in adults for the treatment:

• of loss of bone consistency following cancer (tumoral osteolysis);
• of bone marrow cancer (multiple myeloma);
• of excessive functionality of the parathyroid glands (primary hyperparathyroidism). It is also used in women for the prevention and treatment of loss of bone consistency (osteoporosis) after menopause (period of permanent cessation of menstruation).

2. What you need to know before using NIKLOD

Do not use NIKLOD

• If you are allergic to clodronic acid or 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 other local anaesthetics of the amide type, such as: bupivacaine, mepivacaine, ropivacaine, levobupivacaine.
• If you suffer from a heart condition that causes loss of consciousness (Adam-Stokes syndrome).
• If you suffer from a heart rhythm disorder (Wolff-Parkinson-White syndrome, atrial fibrillation, sinoatrial or atrioventricular or intraventricular block).
• If you have a weak heart that cannot provide the
• blood in adequate quantity to the body (acute heart failure).
• If you suffer from a state of decreased blood volume (hypovolemia)

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

Warnings and precautions
Consult your doctor or pharmacist before using NIKLOD.
Before and during treatment, your doctor will ask you to undergo blood tests to monitor the
function of your kidneys and liver (see section 4. “Possible side effects”). It is
important that you take 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, tell your doctor:

• If you have high levels of calcium in your blood.
• If you suffer from a kidney disease (renal insufficiency).
• If you are being treated with NIKLOD for cancer, or to treat osteoporosis, and you are undergoing dental treatment or are to undergo dental surgery. Also inform your dentist that you are being treated with Niklod (see section 4. Possible side effects), as preventive dental treatment may be necessary.
• If you suffer from heart disease (in particular rhythm disturbances with low frequency and heart failure) or if you have undergone heart surgery.
• If you suffer from a severe liver disease.
• If you, or someone in your family, suffers from a condition that causes a high increase in body temperature following the use of local anaesthetics such as lidocaine (malignant hyperthermia).
• If you experience weakness or pain in the thigh, hip or groin during treatment, as this may be an early symptom of a possible femur fracture (see section
• 4. Possible side effects).
• If you suffer from seizures (epilepsy). Your doctor will monitor you closely for any symptoms.
• If you suffer from respiratory and pulmonary disorders.
• If you suffer from a disease that causes muscle weakness (myasthenia gravis).
• If you have porphyria (a rare hereditary disease of the blood cells that affects the skin and nervous system).

Children and adolescents
The safety and efficacy of the medicine in paediatric 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
medicine.
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 (in particular diclofenac), as kidney problems may occur.
• You are taking aminoglycosides, medicines used to treat infections, as calcium levels in the blood may decrease (hypocalcaemia).
• You are taking estramustine, a medicine used to treat prostate cancer (a gland in men that produces seminal fluid), as concentrations of estramustine in the blood may increase.
• You are taking medicines used for the treatment of heart disorders including irregular heartbeats, such as beta-blockers (e.g. propranolol), or calcium channel blockers (e.g. amiodarone) or sodium channel blockers, as lidocaine may remain in circulation for longer.
• You are taking cimetidine, a medicine used mainly to treat gastritis and gastric ulcer (lesion of the stomach wall); fluvoxamine (a medicine used for depression); medicines for the treatment of viral infections such as ritonavir; medicines for the treatment of bacterial infections such as macrolide antibiotics, such as erythromycin or antibiotics such as ciprofloxacin; medicines for the treatment of fungal infections such as ketoconazole, itraconazole, as this may cause an increase in lidocaine levels in the blood.
• 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 cause a decrease in lidocaine levels in the blood.
• You are being treated with digitalis, medicines used to treat heart rhythm disorders, as this may increase the risk of heart rhythm disorders.
• You are taking medicines used to relax muscles during general anaesthesia, such as suxamethonium.
• The solution is incompatible with alkaline solutions or oxidizing solutions.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you are pregnant or are planning to become pregnant, or if you are breastfeeding,
ask your doctor or pharmacist for advice before using this medicine.
Pregnancy
Avoid using NIKLOD during pregnancy or if you are of childbearing potential and are 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, discontinue breastfeeding during treatment with NIKLOD.
Fertility
It is not known whether clodronic acid and lidocaine have effects on human fertility.

Driving and operating machinery
NIKLOD may cause visual disturbances that may affect your ability to drive vehicles and use
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
vehicles and using machinery.

Important information about some excipients
NIKLODcontains 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 (the main component of table salt) per dose. This is equivalent to 1.6%
of the maximum recommended daily intake with the diet of an adult.

3. How to use NIKLOD

Use this medicine following the doctor's instructions exactly, who will indicate the correct dose,
based on the severity of your condition, and the duration of treatment. If you have any doubts, consult your doctor or
pharmacist (see the DOSE, METHOD AND DURATION OF ADMINISTRATIONsection at the end of
Clodronic acid is eliminated predominantly by the kidneys. Therefore, during treatment with clodronic acid, it is necessary to ensure an adequate fluid intake.

Method of administration
NIKLOD 100 mg + 33 mg injectable solution with lidocaine and NIKOD 200 mg + 40 mg injectable solution
with lidocaine are for intramuscular use only(i.e. to be injected into a muscle). To avoid an
accidental injection into a blood vessel, it is recommended to aspirate before injecting the medicine.
Avoid massaging the injection site.

If you use more NIKLOD than you should
In case of accidental intake of an excessive dose of NIKLOD, immediately contact your doctor or
the nearest hospital.
The symptoms of overdose may consist of:

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

In case of accidental injection into a blood vessel, the following symptoms of lidocaine overdose may occur:

• drowsiness,
• intoxication (state of excessive excitement),
• sedation (physical and mental relaxation),
• loss of sensitivity in some parts of the body (paresthesia),
• muscle spasms (sudden and involuntary contraction of a muscle), uncontrolled body movements (convulsions),
• reduced blood flow to the body (cardiovascular collapse).

Treatment
The doctor will monitor the symptoms with specific therapies.

If you forget to use NIKLOD
Do not use a double dose to make up for a missed dose.

If you stop using NIKLOD
If you have any doubts about the use of 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 vision or eye problems during treatment, STOP therapy and
consult an ophthalmologist.
Immediately inform your doctor if you experience:

• pain or sores in the mouth or jaw and/or mandible (two bones of the face), as this may be the first signs of serious problems (death of the jaw bone tissue and/or mandible), 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)

• lowering of calcium levels in the blood, without symptoms (asymptomatic hypocalcemia),
• diarrhea, nausea, vomiting (usually mild),
• increased levels of transaminases in the blood (test to assess liver function), usually within the normal range. rare (may affect up to 1 in 1,000)
• lowering of calcium levels in the blood, with symptoms (symptomatic hypocalcemia),
• increased level of parathyroid hormone (hormone that regulates calcium levels in the blood) associated with reduced calcium in the blood,
• increased levels of alkaline phosphatase in the blood (test to assess the condition of the bones and liver),
• increased levels of transaminases in the blood (test to assess liver function) more than twice the normal values, without other abnormalities in liver function, allergic reactions that manifest as skin reactions, unusual fracture of the femur (long bone of the leg), especially in patients treated for a long time 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)
• Consult your doctor in case of ear pain, ear discharge and/or ear infection. These episodes may be signs of bone damage in the ear. The following side effects may also occur, for which it is not possible to estimate the frequency:
• effects related to the eyes
• inflammation of the conjunctiva, the membrane that covers the eye and the inside of the eyelids (conjunctivitis)
• inflammation of the eye (episcleritis, scleritis and uveitis). Episcleritis and scleritis have been reported with other drugs belonging to the same class as clodronic acid (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 that manifest as breathing difficulties.
• 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 often with concomitant use of diclofenac). See section 2. Other medicines and NIKLOD.
• effects related to bones and muscles
• severe pain in the bones, joints and muscles. The onset of symptoms varies from days to several months after starting therapy with NIKLOD.
• pain or sore in the mouth or jaw and/or mandible (two bones of the face). This may be the first signs of serious problems (death of the jaw bone tissue and/or mandible), usually associated with tooth extraction and/or local infection (see section 2. Warnings and precautions). In most cases, this has occurred in patients with cancer.
• effects related to the injection site
• pain at the injection site, also considering the duration of therapy.

Side effects specific to lidocaine
The following are side effects that occur with lidocaine, there is not enough data available to establish the frequency of the individual effects listed. Side effects are generally
due to allergic reactions or excessively high concentrations in the blood due to accidental injection into a blood vessel and/or overdose. This can occasionally cause effects
excitement of the central nervous system and occasional depressive cardiovascular effects (see section 2.
Warnings and precautions).

Immune system disorders
Severe allergic reaction (anaphylactoid), swelling of the larynx up to difficulty breathing
(bronchospasm), and low blood pressure (cardiorespiratory collapse) from anaphylactic shock.

Nervous system disorders
Manifestations of excitement or depression associated with dizziness, drowsiness, visual disturbances, tremors
followed by changes in consciousness, convulsions, coma, prolonged contraction of the muscles of the
jaw leading to tight closure of the mandible and jaw (trismus), alteration of the
sensitivity of the limbs or other parts of the body (paresthesia).

Psychiatric disorders
Anxiety, disorientation.

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

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

Gastrointestinal disorders
Nausea, vomiting.

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

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

Skin and subcutaneous tissue disorders
Sudden redness of the skin (various types of skin rashes), skin rash with more or less
itchy blisters (urticaria), itching.

Ear and labyrinth disorders
Ringing in the ears (tinnitus), hypersensitivity to relatively weak noises (hyperacusis).

Reporting of side effects
If you get any side effects, even those not listed in this leaflet, tell your
doctor or pharmacist. You can also report side effects directly through the national reporting system at the address 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 pack after Scad.
The expiry date refers to the last day of that month.
Do not dispose of any medicine in waste water 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 ingredients are Disodium clodronate (disodium salt of clodronic acid) 100 mg and Lidocaine hydrochloride 33 mg.
• The other ingredients are Sodiumbicarbonate (see section 2. NIKLOD contains sodium), water for injections. NIKLOD 200 mg+ 40 mg injectable solution with lidocaine
• The active ingredients are Disodium clodronate (disodium salt of clodronic acid) 200 mg and Lidocaine hydrochloride 40 mg.
• The other ingredients are Sodiumbicarbonate (see section 2. NIKLOD contains sodium), water for injections.

Description of the appearance of NIKLOD and package contents

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 3 or 6 vials for intramuscular use

Marketing Authorisation Holder and Manufacturer
MARKETING AUTHORISATION 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)
Abiogen Pharma SpA – Via Meucci, 36 – Loc. Ospedaletto – PISA
---------------------------------------------------------------------------------------------------------------------------
The following information is intended exclusively for physicians or healthcare professionals:

DOSAGE, ADMINISTRATION AND DURATION OF TREATMENT
Tumoral osteolysis, Multiple myeloma and Primary hyperparathyroidism
The dosage regimen below should be considered as a guideline and may therefore be adapted to the
needs of the individual patient.
a) Attack phase
NIKLOD 300 mg/10 ml concentrate for solution for infusion, 300 mg/day in a single administration by
slow intravenous route for 3-8 days depending on the trend of clinical and laboratory parameters
(calcaemia, hydroxyprolinuria, etc.).
For more information regarding NIKLOD 300 mg/10 ml concentrate for solution for infusion see
b) Maintenance phase
NIKLOD 100mg+ 33 mg injectable solution with lidocaine
100 mg/day by intramuscular route for 2-3 weeks
or, alternatively,
the use of 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 medicine for which an oral clodronate formulation is available must be prescribed.
The duration of treatment, usually long-term, depends on the evolution of the disease.
Periodic re-evaluation of bone resorption parameters is recommended as a guide to judging the
need for continued therapy.

Prevention and treatment of postmenopausal osteoporosis
The dosage depending on the clinical picture and densitometric values may vary as reported below.

Parenteral therapy

NIKLOD100 mg + 33 mg injectable solution with lidocaine
by intramuscular route 100 mg every 7-14 days, for 1 year or more depending on the patient's condition.

NIKLOD200 mg + 40 mg injectable solution with lidocaine
by intramuscular route 200 mg every 14-28 days, for 1 year or more depending on the patient's condition.

NIKLOD200 mg + 40 mg injectable solution with lidocainecan be used in patients who have never started treatment with clodronate.
In case of switching from the administration of NIKLOD 100 mg + 33 mg to NIKLOD 200 mg + 40 mg, the
administration of one vial of NIKLOD 200 mg+ 40 mg every 14 days can be used as an alternative dosage scheme in patients already treated with one vial of 100 mg per week.
The administration of one vial of NIKLOD 200 mg + 40 mg every 28 days can be used as
an alternative dosage scheme in patients already treated with one vial of 100 mg every two weeks.
Alternatively
Oral therapy
NIKLOD is available only in formulations for intramuscular and intravenous infusion use. Therefore
for oral therapy, a medicine for which an
oral clodronate formulation is available must be prescribed.
Duration
The optimal duration of treatment with bisphosphonates for osteoporosis has not been established. The need for
continuous treatment must be re-evaluated in each individual patient periodically depending on the
potential benefits and risks, in particular 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 the drug for the elderly. Clinical studies have included patients over 65 years of age and no specific adverse events have been reported for this age group.
• Patients with renal impairment Clodronate is eliminated primarily by the renal route. Therefore, it must be used with caution in patients with renal impairment.

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

It is recommended to administer clodronate before hemodialysis, to reduce the dose by 50% on non-dialysis days
and to limit the treatment regimen to 5 days. It should be noted that peritoneal dialysis removes
scarcely clodronate from the circulation.
Instructions for use
NIKLOD 100 mg + 33 mg injectable solution with lidocaine and NIKLOD 200 mg + 40 mg injectable solution
are for exclusive intramuscular use: to avoid accidental intravascular injection, it is recommended to
aspirate before injecting the medicine.
Avoid massaging the injection site.
The solution is incompatible with alkaline solutions or oxidizing solutions.
For more information regarding NIKLOD 300 mg/10 ml concentrate for solution for infusion see

NIKLOD 300 mg/10 ml concentrate for solution for infusion

Clodronic acid
Read this leaflet carefully before you are given this medicine becauseit 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 pass it on to others, even if their symptoms are the same as yours, because it could be harmful.
• If you get any side effects, even those not listed in this leaflet, tell 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 that contains clodronic acid, an active ingredient that belongs to a group of
medicines for the treatment of bone diseases, called bisphosphonates.
NIKLOD is used in adults for the treatment of:

• loss of bone consistency following cancer (tumor osteolysis);
• bone marrow cancer (multiple myeloma);
• excessive functionality 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 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 check the
functionality of your kidneys and liver (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, tell your doctor:

• If you have high levels of calcium in your blood.
• If you suffer from a kidney disease (renal insufficiency).
• If you are being treated with NIKLOD to treat cancer and are undergoing dental treatment or need to undergo dental surgery. Also inform your dentist that you are being treated with NIKLOD (see section 4. Possible side effects), as preventive dental treatment may be necessary.
• If you suffer from a liver disease.
• If you experience weakness or pain in the thigh, hip or groin during treatment, as this may 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 NIKLOD
Tell your doctor or pharmacist if you are taking, have recently taken or might take any
other medicine.
This is particularly important if:

• You are taking other bisphosphonates, medicines used to treat bone diseases, as the 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 (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 estramustine concentrations in the blood may increase.
• You are receiving solutions containing divalent cations through a vein (e.g.: Ringer's solution).

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you are pregnant or are planning a pregnancy, or if you are breastfeeding with
breast milk, ask your doctor or pharmacist for advice before this medicine is administered to you.
Pregnancy
Avoid using NIKLOD during pregnancy and if you are of childbearing potential and are not using an
effective contraceptive therapy (medicines used to prevent pregnancy).
Breastfeeding
It is not known whether clodronic acid passes into breast milk. Therefore, during treatment with NIKLOD,
stop breastfeeding.
Fertility
It is not known whether clodronic acid has effects on human fertility.

Driving and using machines
NIKLOD may cause visual disturbances that may affect your ability to drive vehicles and use
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
vehicles and using machinery.

NIKLOD contains sodium
This medicine contains 49.1 mg of sodium
(the main component of table salt) per dose. This is equivalent to 2.46% of the maximum
recommended daily intake with the diet of an adult.
This should be taken into consideration if you suffer from a kidney disease or follow a low-sodium
diet.

3. How to use NIKLOD

Use this medicine following the doctor's instructions exactly, who will indicate the correct dose,
based on the severity of your condition, and the duration of treatment. This medicine will be administered to you
by the doctor or a nurse (see the section DOSE, METHOD AND DURATION OF
Clodronic acid is eliminated predominantly by the kidneys. Therefore, during treatment with clodronic acid, it is necessary to take an adequate amount of fluids. This is particularly important
when NIKLOD is administered through a vein:

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

Method of administration
NIKLOD 300 mg/10 ml concentrate for solution for infusion is for intravenous use onlyand must be
diluted before infusion. It will be administered directly into your veins slowly (2-3 hours).

If you use more NIKLOD than you should
In case of accidental intake of an excessive dose of NIKLOD, immediately contact your doctor or
the nearest hospital.
The symptoms of overdose may consist of:

• increased levels of creatinine in the blood kidney disease (renal dysfunction) (with high doses of clodronic acid administered intravenously)
• elevated levels of nitrogen in the blood (uremia),
• liver damage,
• lowering of calcium levels in the blood (hypocalcemia)

Treatment
The doctor will monitor the symptoms with specific therapies.

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

If you stop using NIKLOD
If you have any doubts about the use of this medicine, contact 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 vision or eye disorders during treatment, STOP therapy and
consult an ophthalmologist.
Immediately inform your doctor if you experience:

• pain or sores in the mouth or jaw and/or mandible (two bones of the face), as this may be the first signs of serious problems (death of bone tissue of the mandible and/or jaw) generally 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)

• decrease in blood calcium levels, without symptoms (asymptomatic hypocalcemia)
• diarrhea, nausea, vomiting (usually mild)
• increase in blood transaminase levels (test to assess liver function), usually within normal limits. rare (may affect up to 1 in 1,000)
• decrease in blood calcium levels, with symptoms (symptomatic hypocalcemia)
• increase in parathyroid hormone levels (hormone that regulates calcium levels in the blood) associated with reduced blood calcium
• increase in alkaline phosphatase levels in the blood (test to assess the condition of bones and liver)
• increase in blood transaminase levels (test to assess liver function) more than twice the normal values, without other abnormalities in liver function
• allergic reactions that manifest as skin reactions
• unusual fracture of the femur (long bone of the leg), especially in patients treated for osteoporosis for a long time. 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)
• Consult your doctor in case of ear pain, ear discharge and/or ear infection. These episodes may be signs of bone damage to the ear.

The following side effects may also occur, for which it is not possible to estimate the frequency:

• effects that affect the eyes
• inflammation of the conjunctiva, the membrane that covers the eye and the inside of the eyelids (conjunctivitis)
• inflammation of the eye (episcleritis, scleritis and uveitis). Episcleritis and scleritis have been reported with other drugs belonging to the same class as clodronic acid (bisphosphonates)
• effects that affect the lungs
• breathing difficulties in patients with asthma sensitive to acetylsalicylic acid (a medicine used to treat fever, pain and inflammation)
• allergic reactions that manifest as respiratory disorders
• effects that affect 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 often with diclofenac). See section 2. Other medicines and NIKLOD.
• effects that affect bones and muscles
• severe pain in bones, joints and muscles. The onset of symptoms varies from days to several months after starting therapy with NIKLOD
• pain or sore in the mouth or jaw and/or mandible (two bones of the face). This may be the first signs of serious problems (death of bone tissue of the mandible and/or jaw), generally associated with tooth extraction and/or local infection (see section 2. Warnings and precautions). In most cases, this has occurred in patients with cancer.
• effects that affect the injection site
• pain at the injection site, also considering the duration of therapy.

Reporting of side effects
If you get any side effects, talk to your
doctor or pharmacist. You can also report side effects directly through 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 that is reported on the pack after Scad.
The expiry date refers to the last day of that month.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to eliminate the
medicines that you no longer use. This will help to protect the environment.

6. Package contents and other information

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

• The active ingredient is Disodium clodronate (disodium salt of clodronic acid) 300 mg
• The other ingredients are: sodiumbicarbonate (see section 2. NIKLOD contains sodium), water for injections.

Description of the appearance of NIKLOD and contents of the pack
NIKLOD is a concentrate for solution for infusion, in a pack of 6 vials for intravenous use

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation 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 doctors or healthcare professionals:
This medicine 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 osteolysis. Multiple myeloma. Primary hyperparathyroidism.
The following dosage regimen should be considered as a guideline and can therefore be adapted to the
needs of the individual patient.
a) Attack phase

NIKLOD 300 mg/10 ml concentrate for solution for infusion,300 mg/day in a single administration by
slow intravenous route for 3-8 days depending on the trend of clinical and laboratory parameters
(calcaemia, hydroxyprolinuria, etc.).
Clodronate is administered as an intravenous infusion of 300 mg (one 10 ml vial)/day diluted
in 500 ml of 0.9% physiological saline solution (sodium chloride 9 mg/ml) or in a 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 intramuscularly for 2-3 weeks).
For more information regarding NIKLOD 100 mg + 33 mg injectable solution with lidocaine
or, alternatively,
the use of an oral clodronate formulation could be considered.
NIKLOD is only available in intramuscular and intravenous infusion formulations. Therefore
for oral therapy a medicine for which an oral clodronate formulation is available must be prescribed.
The duration of treatment, usually long-term, depends on the evolution of the disease.
Periodic re-evaluation of bone resorption parameters is recommended as a guide to judging the
need for continued therapy.

Special populations

• Children The safety and efficacy of the drug in paediatric patients have not been established.
• Elderly There are no specific dosage recommendations for the drug for the elderly. Clinical studies conducted have included patients over 65 years of age and no specific adverse events have been reported for this age group.
• Patients with renal insufficiency

Clodronate is eliminated mainly by the renal route. Therefore, it must be used with caution in
patients with renal insufficiency.

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

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