Clobiox

Package leaflet: Information for the user

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

disodium clodronate and lidocaine hydrochloride
Equivalent medicine
Please read all of this leaflet carefully before you start 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 may be harmful.
• If you experience any side effects, including 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 use 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 Clobiox is and what it is used for

Clobiox is a medicine that contains clodronic acid (in the form of clodronate disodium), an active substance belonging to a group of medicines used to treat bone diseases called bisphosphonates, and lidocaine, an active substance belonging to a group of medicines known as "local anaesthetics".
Clobiox is used in adults for the treatment:

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

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

2. What you need to know before using 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 to other amide-type local anesthetics such as, for example: bupivacaine, mepivacaine, ropivacaine, levobupivacaine.
• If you suffer from a heart condition causing loss of consciousness (Adam-Stokes syndrome).
• If you suffer from a heart rhythm disorder (Wolff-Parkinson-White syndrome, atrial fibrillation, sinoatrial, atrioventricular or intraventricular block).
• If you have a weak heart unable to supply sufficient blood to the body (acute heart failure).
• If you suffer from a condition of reduced blood volume (hypovolemia).

The medicine is for intramuscular use only (i.e. injected into a muscle) and must not
be administered into a blood vessel (intravenously). Accidental injection into a vein increases the risk of severe adverse reactions due to high blood levels of the local anesthetic lidocaine (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 acute phase treatment.

Before and during treatment, your doctor may ask you to undergo blood tests to monitor kidney and liver function (see section 4. Possible side effects). It is important that you drink adequate amounts of fluids during treatment with this medicine, especially if you have kidney problems (see section 3. How to use Clobiox).

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 Clobiox for cancer or osteoporosis and are undergoing dental treatment or need 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 diseases (particularly heart rhythm disorders with low heart rate and heart failure) or if you have had heart surgery.
• If you suffer from 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 during treatment you experience weakness or pain in the thigh, hip or groin, as this could be an early symptom of a possible femur fracture (see section 4. Possible side effects).
• If you suffer from seizures (epilepsy). Your doctor will closely monitor you for any possible symptoms.
• If you 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 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 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 (particularly diclofenac), as kidney problems may occur.
• You are taking aminoglycosides, medicines used to treat infections, as calcium levels in the blood may decrease (hypocalcemia).
• You are taking estramustine, a medicine used to treat prostate cancer (a gland in men that produces seminal fluid), as blood 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 circulation longer.
• You are taking cimetidine, a medicine mainly used to treat gastritis and gastric ulcer (a lesion of the stomach wall); fluvoxamine (a medicine used for depression); antiviral medicines such as ritonavir; medicines used to treat infections such as macrolide antibiotics (erythromycin) or other antibiotics such as ciprofloxacin; antifungal medicines such as ketoconazole, itraconazole, as blood levels of lidocaine may increase.
• You are taking barbiturates such as phenobarbital; medicines used to treat epilepsy such as carbamazepine; phenytoin; primidone; oral contraceptives or hormone replacement therapy, as blood levels of lidocaine may decrease.
• You are being treated with digitalis, medicines used to treat heart rhythm disorders, as the risk of heart rhythm disturbances may increase.
• You are taking medicines used to relax muscles during general anesthesia, such as suxamethonium. The solution is incompatible with alkaline solutions or oxidizing solutions.

Pregnancy, breast-feeding and fertility

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

Pregnancy

Avoid using Clobiox during pregnancy and if you are of childbearing age and not using contraception (medicines used to prevent pregnancy).

Breast-feeding

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, breastfeeding should be discontinued.

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 could affect your ability to drive or use machinery.

If you experience one or more of the symptoms listed in section 4 or if you use more Clobiox than you should, avoid driving and using machinery.

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 (main component of table salt) per dose. This corresponds to 2% of the maximum recommended daily dietary intake for an adult.

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

3. How to use Clobiox

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. 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 mainly eliminated via the kidneys. Therefore, adequate fluid intake must be ensured during treatment with clodronic acid.

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

If you accidentally take too much Clobiox, contact your doctor or go to the nearest hospital immediately.

Symptoms of overdose may include:

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

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

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

Treatment

Your doctor will manage the symptoms with specific therapies.

If you forget to use Clobiox

Do not use a double dose to make up for the forgotten dose.

If you stop using Clobiox

If you have any doubts about using this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
If you experience any eye or vision disturbances during treatment,
STOP the treatment and consult an ophthalmologist.
Inform your doctor immediately if you experience:

• pain or sores in the mouth or jaw and/or maxilla (two facial bones), as these may be early signs of serious problems (bone death of the jaw and/or maxilla), usually associated with tooth extraction and/or local infection (see section 2. Warnings and precautions).
  The possible side effects are listed below by frequency:

Common (may affect up to 1 in 10 people)

• diarrhoea, nausea, vomiting (usually mild in intensity),
• decrease in blood calcium levels without symptoms (asymptomatic hypocalcaemia),
• increase in blood transaminase levels (a test to assess liver function), usually within normal values.

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

• decrease in blood calcium levels with symptoms (symptomatic hypocalcaemia),
• increase in parathyroid hormone levels (a hormone regulating calcium levels) in blood, associated with low blood calcium,
• increase in alkaline phosphatase levels in blood (a test to assess bone and liver condition),
• increase in blood transaminase levels (a test to assess liver function) more than twice the upper normal limit, without other liver function abnormalities,
• allergic reactions manifesting as skin reactions,
• unusual femur fracture (long leg bone), particularly in patients on long-term treatment for osteoporosis. Contact your doctor if you experience pain or
  weakness in the thigh, hip, or groin, as this could be an early sign of a possible femur fracture.

Very rare (may affect up to 1 in 10,000 people)

• consult your doctor if you experience ear pain, ear discharge, and/or ear infection. These episodes could be signs of bone damage in the ear.

The following side effects may also occur, for which the frequency cannot be estimated from the available data:
Effects concerning the eyes

• inflammation of the conjunctiva, the membrane covering the eye and the inner surface of the eyelids (conjunctivitis);
• inflammation of the eye (episcleritis, scleritis, and uveitis). Episcleritis and scleritis have been reported with other drugs belonging to the same class as clodronic acid (a class adverse reaction of bisphosphonates).

Effects concerning the lungs

• breathing difficulties in patients with asthma sensitive to acetylsalicylic acid (a medicine used to treat fever, pain, and inflammation).
• allergic reactions manifesting as breathing problems.

Effects concerning the kidneys and urinary tract

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

Effects concerning bones and muscles

• severe bone, joint, and muscle pain. The onset of symptoms varies from days to several months after starting treatment with Clobiox.
• pain or sores in the mouth or jaw and/or maxilla (two facial bones). These may be early signs of serious problems (bone death of the jaw and/or maxilla), usually associated with tooth extraction and/or local infection (see section 2. Warnings and precautions). In most cases, this has occurred in patients with cancer.

Effects at the injection site

• tenderness at the injection site, possibly related to the duration of treatment.

Side effects specific to lidocaine

• Listed below are the side effects associated with lidocaine. There are insufficient data to determine the frequency of individual events listed. Side effects are generally due to either allergic reactions or excessively high blood concentrations resulting from accidental intravascular injection and/or overdose. This may occasionally cause central nervous system excitation and occasional cardiovascular depression (see section 2. Warnings and precautions).

Immune system disorders

• Severe allergic reaction (anaphylactoid), swelling of the larynx leading to breathing difficulty (bronchospasm), and drop in blood pressure (cardiorespiratory collapse) due to anaphylactic shock.

Nervous system disorders

• Symptoms of excitation or depression associated with dizziness, drowsiness, visual disturbances, tremors, followed by changes in consciousness, seizures, coma, prolonged contraction of the jaw muscles leading to tight closure of the
  jaw and maxilla (trismus), altered sensation in limbs or other body parts (paraesthesia).

Psychiatric disorders

• Anxiety, disorientation.

Cardiac disorders

• Slowing of the heart rate (bradycardia), changes in heart rhythm (arrhythmias), myocardial depression up to cardiac arrest.

Eye disorders

• Pupil dilation (mydriasis), blurred vision, double vision (diplopia).

Gastrointestinal disorders

• Nausea, vomiting.

Respiratory, thoracic and mediastinal disorders

• Difficulty breathing (dyspnoea), 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 reduced blood flow (circulatory collapse).

Skin and subcutaneous tissue disorders

• Sudden reddening of the skin (various types of skin rashes), itchy rash with wheals (urticaria), itching.

Ear and labyrinth disorders

• Ringing in the ears (tinnitus), increased sensitivity to relatively low sounds (hyperacusis).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse.
You can also report side effects directly via the website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Clobiox

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 Clobiox contains

• Clobiox 100 mg + 33 mg injectable solution with lidocaine

  • The active substances are disodium clodronate (disodium salt of clodronic acid, as tetrahydrate) 100 mg and lidocaine hydrochloride (as monohydrate) 33 mg.
  • The other components are sodium hydrogen carbonate (see section 2. Clobiox contains sodium), water for injections.

• Clobiox 200 mg + 40 mg injectable solution with lidocaine

  • The active substances are disodium clodronate (disodium salt of clodronic acid, as tetrahydrate) 200 mg and lidocaine hydrochloride (as monohydrate) 40 mg.
  • The other components are sodium hydrogen carbonate (see section 2. Clobiox contains sodium), water for injections.

Description of the appearance of Clobiox and contents of the pack
Clobiox 100 mg + 33 mg injectable solution with lidocaine: injectable solution in a pack of 6 vials for intramuscular use. Clear, colourless solution, free from visible particles.
Clobiox 200 mg + 40 mg injectable solution with lidocaine: injectable solution in a pack of 3 vials for intramuscular use. Clear, colourless solution, free from visible particles.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
LANOVA FARMACEUTICI S.r.l
Via Conca D’oro, 212
00141 Rome
Italy

Manufacturer
Esseti Farmaceutici S.r.l.
Via Campobello, 15
00071 Pomezia (Rome)
Italy

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The following information is intended exclusively for doctors and healthcare professionals:
DOSAGE, METHOD AND DURATION OF ADMINISTRATION
Tumour-induced osteolysis. Multiple myeloma. Primary hyperparathyroidism
The following dosage regimen is indicative and may therefore be adjusted according to the individual patient's needs.
Initial phase: For the initial phase, the physician will administer a clodronic acid-based medicinal product by intravenous infusion, as Clobiox is available only in a formulation for intramuscular use.
Maintenance phase: Clobiox 100 mg + 33 mg injectable solution with lidocaine (one vial daily by intramuscular injection for 2-3 weeks).
These treatment cycles may be repeated at variable intervals depending on the progression of the disease.
Alternatively, the physician may prescribe an oral clodronic acid-based medicinal product, as Clobiox is available only in a formulation for intramuscular use.
The duration of treatment, usually long-term, depends on the progression of the disease.
Periodic re-evaluation of bone resorption parameters is recommended as a guide to assess the need for continuing therapy.

Prevention and treatment of postmenopausal osteoporosis
Dosage may vary according to clinical condition and bone mineral density values as follows:
Clobiox 100 mg + 33 mg injectable solution with lidocaine:
100 mg + 33 mg by intramuscular injection every 7-14 days, for 1 year or longer depending on the patient's condition.
Clobiox 200 mg + 40 mg injectable solution with lidocaine:
200 mg + 40 mg by intramuscular injection every 14-28 days, for 1 year or longer depending on the patient's condition.
Clobiox 200 mg + 40 mg injectable solution with lidocaine may be used in patients who have never previously started clodronate treatment.
When switching from Clobiox 100 mg + 33 mg injectable solution with lidocaine to Clobiox 200 mg + 40 mg injectable solution with lidocaine, administration of one vial of Clobiox 200 mg + 40 mg every 14 days may be used as an alternative dosage regimen in patients already receiving one 100 mg vial weekly.
Administration of one vial of Clobiox 200 mg + 40 mg every 28 days may be used as an alternative dosage regimen in patients already receiving one 100 mg vial every two weeks.
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be periodically reassessed for each individual patient based on potential benefits and risks, particularly after 5 years or more of use.

Special populations

• Children
  The safety and efficacy of the medicinal product in paediatric 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 in this group.

• Patients with renal impairment
  Clodronate is primarily eliminated via the kidneys. Therefore, it must be used with caution in patients with renal impairment. Dose reduction of clodronate is recommended as follows:

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