CLOBIOX 100 mg/33 mg Injectable Solution

Зміст інструкції

1. Clobiox 100 mg + 33 mg injectable solution with lidocaine, 200 mg + 40 mg injectable solution with lidocaine
   1. What is Clobiox and what is it used for
   2. What you need to know before you use Clobiox
   3. How to use Clobiox
   4. Possible side effects
   5. How to store Clobiox
   6. Package Contents and Other Information

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

disodium clodronate and lidocaine hydrochloride
Equivalent medicine

Read this leaflet carefully before you start to take 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 pass it on to others, even if their symptoms are the same as yours, as it may 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 Clobiox is and what it is used for
• 2. What you need to know before you take Clobiox
• 3. How to use Clobiox
• 4. Possible side effects
• 5. How to store Clobiox
• 6. Contents of the pack and other information

1. What is Clobiox and what is it used for

Clobiox is a medicine that contains clodronic acid (in the form of clodronate disodium), an
active ingredient that belongs to a group of drugs for the treatment of bone diseases, called
bisphosphonates, and lidocaine, an active ingredient that belongs to the group of
drugs called “local anesthetics”.
Clobiox is used in adults for the treatment:

• of loss of bone consistency following cancer (tumour 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 you use Clobiox

Do not use Clobiox

• 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 Clobiox.
• If you are allergic to lidocaine or other local anaesthetics of the amide type such as, for example: bupivacaine, mepivacaine, ropivacaine, levobupivacaine.
• If you suffer from a heart condition that causes loss of consciousness (Adam-Stokes syndrome).
• If you suffer from an irregular heartbeat (Wolff-Parkinson-White syndrome, atrial fibrillation, sinoatrial or atrioventricular or intraventricular block).
• If you have a weak heart that cannot provide enough blood to the body (acute heart failure).
• If you suffer from a condition 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
Clobiox than you should).

Warnings and precautions
Talk to your doctor or pharmacist before using Clobiox.
Clobiox is not suitable for the acute phase.
Before and during treatment, your doctor may 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 drink an adequate amount of fluids during
treatment with this medicine, especially if you have kidney problems (see section 3.
How to use Clobiox).
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 Clobiox to treat cancer or osteoporosis, and you are undergoing dental treatment or must undergo dental surgery. Also inform your dentist that you are being treated with Clobiox (see section 4. Possible side effects), as preventive dental treatment may be necessary.
• If you suffer from heart disease (in particular, irregular heartbeat with low frequency and heart failure) or if you have undergone heart surgery.
• If you suffer from a 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 condition that causes muscle weakness (myasthenia gravis).
• If you have porphyria (a rare hereditary blood cell disease 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 Clobiox
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 the concomitant use of Clobiox with other bisphosphonates is contraindicated (see section
• 2. Do not use Clobiox).
• 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 estramustine concentrations in the blood may increase.
• You are taking medicines used to treat 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 stomach ulcers (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 infections such as macrolide antibiotics (erythromycin) or other 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 may be pregnant or are planning a pregnancy, or if you are breastfeeding
with breast milk, ask your doctor or pharmacist for advice before taking this
medicine.

Pregnancy
Avoid using Clobiox during pregnancy and if you are of childbearing potential and are not using contraceptive therapy (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 Clobiox, stop
breastfeeding.

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

Driving and using machines
Clobiox may cause visual disturbances that may affect your ability to drive vehicles
and use machines.
If you experience one or more symptoms listed in section 4 or if you use more Clobiox than you should, avoid
driving vehicles and using machines.

Clobiox contains sodium
Clobiox 100 mg + 33 mg injectable solution with lidocaine contains 17.22 mg of sodium per
dose. This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e.
essentially ‘sodium-free’.
Clobiox 200 mg + 40 mg injectable solution with lidocaine contains 32.90 mg of sodium
(the main component of table salt) per dose. This is equivalent to 2% 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 Clobiox

Use this medicine following exactly the instructions of your doctor, who will indicate
the correct dose, based on the severity of your illness, and the duration of treatment. If you have doubts
consult your doctor or pharmacist (see the section DOSE, METHOD AND TIME OF
Clodronic acid is eliminated predominantly by the kidneys. Therefore, during the
treatment with clodronic acid it is necessary to ensure an adequate amount of fluids.

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

If you use more Clobiox than you should
In case of accidental intake of an excessive dose of Clobiox, 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 contractions 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 Clobiox
Do not use a double dose to make up for a missed dose.

If you stop using Clobiox
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 everyone will experience them.
If you experience vision or eye disturbances 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 an early sign of serious problems (death of the jaw bone tissue and/or mandible), 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)

• diarrhea, nausea, vomiting (usually mild),
• lowering of calcium levels in the blood, without symptoms (asymptomatic hypocalcemia),
• increased levels of transaminases in the blood (test to assess liver function), usually within normal limits.

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

• 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 bone and liver conditions),
• 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 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 people)

• 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 (bisphosphonate class adverse reaction). 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 breathing difficulties. 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 concomitant use of diclofenac). See section 2. Other medicines and Clobiox. effects that affect the bones and muscles
• severe pain in bones, joints and muscles. The onset of symptoms varies from days to several months after starting therapy with Clobiox.
• pain or sore in the mouth or jaw and/or mandible (two bones of the face). This may be an early sign of serious problems (death of the jaw bone tissue and/or mandible), 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
• painfulness 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 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 excitatory effects 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 a drop in blood pressure (cardiorespiratory collapse) from anaphylactic shock. Nervous system disorders
• Manifestations of excitation 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), altered sensitivity of the limbs or other parts of the body (paresthesia).

Psychiatric disorders

• Anxiety, disorientation Cardiac disorders
• slowing of the heart rate (bradycardia), irregular heartbeat (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 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 experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist or nurse. You can also report side effects directly through the address 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 Clobiox

This medicine does not require any particular 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 package 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 medicines that you no longer use. This will help to protect the environment.

6. Package Contents and Other Information

What Clobiox Contains

• Clobiox 100 mg + 33 mg injectable solution with lidocaine
• The active ingredients are disodium clodronate (disodium salt of clodronic acid, as tetrahydrate) 100 mg and lidocaine hydrochloride (as monohydrate) 33 mg
• The other ingredients are sodium hydrogen carbonate (see section 2. Clobiox contains sodium), water for injections.
• Clobiox 200 mg + 40 mg injectable solution with lidocaine
• The active ingredients are disodium clodronate (disodium salt of clodronic acid, as tetrahydrate) 200 mg and lidocaine hydrochloride (as monohydrate) 40 mg.
• The other ingredients are sodium hydrogen carbonate (see section 2. Clobiox contains sodium), water for injections.

Description of the Appearance of Clobiox and Package Contents
Clobiox 100 mg + 33 mg injectable solution with lidocaine:injectable solution in
pack of 6 vials for intramuscular use. Clear, colorless solution, free from visible
particles.

Clobiox 200 mg + 40 mg injectable solution with lidocaine:injectable solution in
pack of 3 vials for intramuscular use. Clear, colorless solution, free from visible
particles.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Esseti Farmaceutici S.r.l
Via R. De Cesare 7
Napoli 80132
Italy

Manufacturer
Esseti Farmaceutici S.r.l.
Via Campobello, 15
00071 Pomezia (Roma)
Italy
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The following information is intended exclusively for doctors and healthcare professionals:

DOSAGE, ADMINISTRATION METHOD AND DURATION OF TREATMENT
Tumor osteolysis. Multiple myeloma. Primary hyperparathyroidism.
The following dosage scheme should be considered as a guideline and may therefore be
adapted to the needs of the individual patient.
Attack phase: For the attack phase, the doctor will administer a medicine based on clodronic
acid for intravenous infusion, as Clobiox is only available in the formulation
for intramuscular use..
Maintenance phase: Clobiox 100 mg + 33 mg injectable solution with lidocaine (one
vial per day intramuscularly for 2-3 weeks).
These treatment cycles can be repeated at variable intervals depending on
the evolution of the disease.
Alternatively, the doctor may administer a medicine based on clodronic acid for
oral use, as Clobiox is only available in the formulation for intramuscular use.
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
for judging the need for continued therapy.

Prevention and treatment of postmenopausal osteoporosis
The dosage depending on the clinical picture and mineralometric values, may vary as
reported below:

Clobiox 100 mg + 33 mg injectable solution with lidocaine:
intramuscularly 100 mg + 33 mg every 7-14 days, for 1 year or more depending on the
patient's conditions.

Clobiox 200 mg + 40 mg injectable solution with lidocaine:
intramuscularly 200 mg + 40 mg every 14-28 days, for 1 year or more depending on the
patient's conditions.
Clobiox 200 mg + 40 mg injectable solution with lidocaine can be used in
patients who have never started treatment with clodronate.
In case of switching from the administration of Clobiox 100 mg + 33 mg injectable solution
with lidocaine to Clobiox 200 mg + 40 mg injectable solution with lidocaine, the
administration of one vial of Clobiox 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 Clobiox 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.
The optimal duration of treatment with bisphosphonates for osteoporosis has not been established. The
need for continued treatment must be re-evaluated in each individual patient
periodically 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 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 insufficiency Clodronate is eliminated mainly by the renal route. Therefore, it must be used with caution in patients with renal insufficiency. 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 scheme 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.