CLONAT

Package leaflet: Information for the user

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

Disodium clodronate and lidocaine hydrochloride
Generic medicine
Please read all of 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 other people, even if they have the same symptoms as yours, because it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

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

1. What Clonat is and what it is used for

Clonat is a medicine containing clodronic acid (in the form of clodronate disodium), an active substance that belongs to a group of drugs used to treat bone diseases, called bisphosphonates, and lidocaine, an active substance that belongs to a group of medicines known as "local anaesthetics".

Clonat is used in adults for the treatment of:

• bone softening 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 softening (osteoporosis) after the menopause (the period of permanent menstrual cessation).

2. What you need to know before using Clonat

Do not use Clonat

• 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 Clonat.
• If you are allergic to lidocaine or to other amide-type local anaesthetics such as, for example: bupivacaine, mepivacaine, ropivacaine, levobupivacaine.
• If you have a heart condition causing loss of consciousness (Adam-Stokes syndrome).
• If you have a heart rhythm disorder (Wolff-Parkinson-White syndrome, atrial fibrillation, sino-atrial, atrioventricular or intraventricular block).
• If you have a weak heart unable to supply sufficient blood to the body (acute heart failure).
• If you have a condition characterized by 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 anaesthetic lidocaine (see section 3. If you use more Clonat than you should).

Warnings and precautions
Talk to your doctor or pharmacist before using Clonat.

Clonat 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 fluid during treatment with this medicine, especially if you have kidney problems (see section 3. How to use Clonat).

In particular, inform your doctor:

• If you have high levels of calcium in your blood.
• If you have kidney disease (renal insufficiency).
• If you are being treated with Clonat for cancer or osteoporosis and are undergoing dental treatment or need dental surgery. Also inform your dentist that you are being treated with Clonat (see section 4. Possible side effects), as preventive dental treatment may be necessary.
• If you have heart diseases (particularly rhythm disorders with slow heart rate and heart failure) or have undergone heart surgery.
• If you have liver disease.
• If you or someone in your family has a condition causing a marked increase in body temperature following the use of local anaesthetics such as lidocaine (familial malignant hyperthermia).
• If you experience thigh, hip or groin pain or weakness during treatment, 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 symptoms.
• If you have respiratory or pulmonary disorders.
• If you have a disease causing muscle weakness (myasthenia gravis).
• If you have porphyria (a rare inherited blood cell disorder affecting the skin and nervous system).

Children and adolescents
The safety and efficacy of this medicine in paediatric patients have not been established.

Other medicines and Clonat
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 Clonat with other bisphosphonates is contraindicated (see section 2. Do not use Clonat).
• 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 blood calcium levels may decrease (hypocalcaemia).
• You are taking estramustine, a medicine used to treat prostate cancer (a gland in men that produces seminal fluid), as blood levels of estramustine may increase.
• You are taking medicines used to treat heart disorders including irregular heartbeats, such as beta-blockers (e.g. propranolol), calcium channel blockers (e.g. amiodarone) or sodium channel blockers, as lidocaine may remain in circulation longer.
• You are taking cimetidine, a medicine mainly used to treat gastritis and gastric ulcer (stomach wall lesion); fluvoxamine (a medicine used for depression); medicines for treating viral infections such as ritonavir; medicines for treating infections such as macrolide antibiotics (erythromycin) or other antibiotics such as ciprofloxacin; medicines for treating fungal infections 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 anaesthesia, such as suxamethonium.

The solution is incompatible with alkaline solutions or oxidizing solutions.

Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine.

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

Breastfeeding
It is not known whether clodronic acid passes into breast milk, whereas lidocaine is excreted in breast milk in small amounts. Therefore, breastfeeding should be discontinued during treatment with Clonat.

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

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

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

Clonat contains sodium
Clonat 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’.

Clonat 200 mg + 40 mg injectable solution for intramuscular use with lidocaine contains 32.90 mg of sodium (main component of table salt) per dose. This corresponds to 2% 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.

3. How to use Clonat

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 Leaflet).
Clodronic acid is predominantly eliminated via the renal route. Therefore, adequate fluid intake must be ensured during treatment with clodronic acid.
Method of administration
Clonat 100 mg + 33 mg injection solution with lidocaine and Clonat 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.
Avoid massaging the injection site.
If you use more Clonat than you should
If you accidentally take an excessive dose of Clonat, 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 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 Clonat
Do not use a double dose to make up for the missed dose.
If you stop using Clonat
If you have any doubts about using this medicine, consult your doctor or pharmacist.

4. Possible side effects

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

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

Common (may affect up to 1 in 10 people)

• diarrhoea, nausea, vomiting (usually mild in intensity),
• decreased levels of calcium in the blood, without symptoms (asymptomatic hypocalcaemia),
• increased levels of transaminases in the blood (a test to assess liver function), usually within normal limits.

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

• decreased levels of calcium in the blood, with symptoms (symptomatic hypocalcaemia),
• increased levels of parathyroid hormone (a hormone that regulates calcium levels) in the blood, associated with low blood calcium,
• increased levels of alkaline phosphatase in the blood (a test to assess bone and liver condition),
• increased levels of transaminases in the blood (a test to assess liver function) more than twice the upper normal limit, without other abnormalities in liver function,
• allergic reactions manifesting as skin reactions,
• unusual femur fracture (long bone of the leg), particularly in patients receiving long-term treatment for osteoporosis. Contact your doctor if you experience pain or weakness in the thigh, hip, or groin, as this 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 frequency cannot be estimated:

Effects related to the eyes

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

Effects related to the lungs

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

Effects related to the kidneys and urinary tract

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

Effects related to bones and muscles

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

Effects related to the injection site

• tenderness at the injection site, particularly considering 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 the individual effects listed. Side effects are generally due to either allergic reactions or excessively high blood concentrations resulting from accidental intravascular injection and/or overdose. This may occasionally cause central nervous system excitation and occasional cardiovascular depression (see section 2. Warnings and precautions).

Immune system disorders

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

Nervous system disorders

• Signs of excitation or depression associated with dizziness, drowsiness, visual disturbances, tremors followed by changes in consciousness, seizures, coma, prolonged contraction of 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

• Slow 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 eruptions), itchy rash with raised bumps (urticaria), itching.

Ear and labyrinth disorders

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

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please tell your doctor, pharmacist, or nurse. You can also report side effects directly via
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 Clonat

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 Clonat contains
Clonat 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.
• Other components: sodium hydrogen carbonate (see section 2. Clonat contains sodium), water for injectable preparations.

Clonat 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 40 mg (as monohydrate).
• Other components: sodium hydrogen carbonate (see section 2. Clonat contains sodium), water for injectable preparations.

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

Marketing Authorisation Holder and Manufacturer
S.F. Group S.r.l.
Via Tiburtina, 1143
Rome 00156
Italy

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

The following information is intended exclusively for physicians and healthcare professionals:
DOSAGE, METHOD AND DURATION OF ADMINISTRATION

Tumour-induced osteolysis. Multiple myeloma. Primary hyperparathyroidism
The dosing regimen described below is intended as a general guide and may therefore be adjusted according to the individual patient's needs.

Initial phase: For the initial phase, the physician will administer a medicinal product containing clodronic acid for intravenous infusion, since Clonat is available only in a formulation for intramuscular use.

Maintenance phase: Clonat 100 mg + 33 mg injectable solution with lidocaine (one vial daily for 2-3 weeks).
These treatment cycles may be repeated at variable intervals depending on the course of the disease.

Alternatively, the physician may prescribe an oral medicinal product based on clodronic acid, since Clonat is available only in a formulation for intramuscular use.

The duration of treatment, which is 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:

Clonat 100 mg + 33 mg injectable solution with lidocaine:
Intramuscular administration: 100 mg + 33 mg every 7–14 days, for 1 year or longer depending on the patient's condition.

Clonat 200 mg + 40 mg injectable solution with lidocaine:
Intramuscular administration: 200 mg + 40 mg every 14–28 days, for 1 year or longer depending on the patient's condition.

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

When switching from Clonat 100 mg + 33 mg injectable solution with lidocaine to Clonat 200 mg + 40 mg injectable solution with lidocaine, administration of one vial of Clonat 200 mg + 40 mg every 14 days may be used as an alternative dosing regimen in patients already receiving one 100 mg vial weekly.

Administration of one vial of Clonat 200 mg + 40 mg every 28 days may be used as an alternative dosing regimen in patients already receiving one 100 mg vial every two weeks.

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: No specific dosage recommendations are required for elderly patients. Clinical studies have included patients over 65 years of age, and no age-specific adverse events have been reported.
• Patients with renal impairment: Clodronate is primarily eliminated via the renal route. Therefore, it must be used with caution in patients with renal impairment. Dose reduction of clodronate is recommended as follows:

It is recommended to administer clodronate before hemodialysis, to reduce the dose by 50% on dialysis-free days, and to limit the treatment schedule to 5 days. It should be noted that peritoneal dialysis removes clodronate poorly from the circulation.
The solution is incompatible with alkaline solutions or oxidizing solutions.