Madras

Package leaflet: Information for the user

Madras 100 mg + 33 mg injection solution with lidocaine, 200 mg + 40 mg injection solution with lidocaine

Disodium clodronate and hydrochloride lidocaine
Generic medicine
Please read all of this leaflet carefully before taking 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, because it could be dangerous.
• If you experience any adverse reaction, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet

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

1. What Madras is and what it is used for

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

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

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

2. What you need to know before using Madras

Do not use Madras

• 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 Madras.
• 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 adequate blood flow 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. 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 high blood levels of the local anesthetic lidocaine (see section 3. If you use more Madras than you should).
Warnings and precautions
Talk to your doctor or pharmacist before using Madras.
Madras is not suitable for the acute phase.
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 Madras).
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 Madras for cancer or osteoporosis, and are undergoing dental treatment or need to undergo dental surgery. Also inform your dentist that you are being treated with Madras (see section 4. Possible side effects), as preventive dental treatment may be required.
• If you suffer from heart diseases (particularly rhythm disorders with low heart rate and heart failure) or if you have undergone heart surgery.
• If you suffer from liver disease.
• If you or someone in your family suffers from a condition causing a marked increase in body temperature following the use of local anesthetics such as lidocaine (malignant familial hyperthermia).
• If you experience weakness or pain in the thigh, hip or groin during treatment, as this could be an early symptom of a possible femoral fracture (see section 4. Possible side effects).
• If you suffer from seizures (epilepsy). Your doctor will closely monitor you for any possible symptoms.
• If you suffer from respiratory or pulmonary disorders.
• If you suffer from 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 the medicine in pediatric patients have not been established.
Other medicines and Madras
Inform your doctor or pharmacist if you are currently 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 Madras with other bisphosphonates is contraindicated (see section 2. Do not use Madras).
• 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 (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 in the stomach wall); fluvoxamine (a medicine used for depression); antiviral medicines such as ritonavir; medicines for treating infections such as macrolide antibiotics (erythromycin) or other antibiotics like 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, breastfeeding and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
Avoid using Madras during pregnancy and if you are of childbearing age and not using contraceptive therapy (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 Madras.
Fertility
It is not known whether clodronic acid and lidocaine have effects on human fertility.
Driving and using machines
Madras may cause visual disturbances that could affect your ability to drive or operate machinery.
If you experience one or more of the symptoms listed in section 4 or if you use more Madras than you should, avoid driving and operating machinery.
Madras contains sodium
Madras 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'.
Madras 200 mg + 40 mg intramuscular injectable solution with lidocaine contains 32.90 mg of sodium (the 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 account if you suffer from kidney disease or are on a low-sodium diet.

3. How to use Madras

Use this medicine exactly as directed 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 Patient Information Leaflet).
Clodronic acid is primarily eliminated via the kidneys. Therefore, adequate fluid intake must be ensured during treatment with clodronic acid.

Method of administration
Madras 100 mg + 33 mg injectable solution with lidocaine and Madras 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 Madras than you should
If you accidentally take too high a dose of Madras, contact your doctor or 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 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 Madras
Do not take a double dose to make up for the forgotten dose.

If you stop using Madras
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 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 tissue 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),
• decreased blood calcium levels without symptoms (asymptomatic hypocalcaemia),
• increased blood transaminase levels (a test to assess liver function), usually within normal limits.

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

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

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

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

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

• inflammation of the conjunctiva, the membrane covering the eye and inner eyelids (conjunctivitis);
• eye inflammation (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 aspirin-sensitive asthma (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 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 Madras.
  Effects related to bones and muscles
• severe bone, joint, and muscle pain. The onset of symptoms varies from days to several months after starting Madras 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 with prolonged treatment.

Side effects specific to lidocaine

• Listed below are side effects associated with lidocaine. There are insufficient data to determine the frequency of the individual side 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 excitatory effects and occasional cardiovascular depressive effects (see section 2. Warnings and precautions).

Immune system disorders

• Severe allergic reaction (anaphylactoid), laryngeal swelling leading to breathing difficulty (bronchospasm), and drop in blood pressure (cardiorespiratory collapse) due to anaphylactic shock.
  Nervous system disorders
• Excitatory or depressive manifestations associated with dizziness, drowsiness, visual disturbances, tremors, followed by changes in consciousness, seizures, coma, prolonged contraction of the jaw muscles leading to tight closure of the jaw and maxilla (trismus), altered sensation in limbs or other body parts (paraesthesia).
  Psychiatric disorders
• Anxiety, disorientation
  Cardiac disorders
• slowed heart rate (bradycardia), heart rhythm disturbances (arrhythmias), myocardial depression up to cardiac arrest.
  Eye disorders
• Pupil dilation (mydriasis), blurred vision, double vision (diplopia).
  Gastrointestinal disorders
• Nausea, vomiting.
  Respiratory, thoracic and mediastinal disorders
• Difficulty breathing (dyspnoea), reduced respiratory rate (respiratory depression).
  Vascular disorders
• Low blood pressure (hypotension), high blood pressure (hypertension), interruption of normal blood circulation due to cardiac arrest and reduced blood flow (circulatory collapse).
  Skin and subcutaneous tissue disorders
• Sudden skin redness (various types of skin rashes), itchy rash with wheals (urticaria), itching.
  Ear and labyrinth disorders
• Ringing in the ears (tinnitus), increased sensitivity to relatively quiet 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
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 Madras

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 no longer required. This will help protect the environment.

6. Package contents and other information

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

Madras 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. Madras contains sodium), water for injections.

Description of the appearance of Madras and contents of the pack
Madras 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.
Madras 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 Authorization 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

Tumoral osteolysis. Multiple myeloma. Primary hyperparathyroidism
The following dosage regimen is indicative and may therefore be adjusted according to the individual needs of the patient.

Initial phase: For the initial phase, your doctor will administer a medicinal product containing clodronic acid by intravenous infusion, as Madras is available only in an intramuscular formulation.

Maintenance phase: Madras 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 progression of the disease.
Alternatively, your doctor may prescribe an oral medicinal product based on clodronic acid, as Madras is available only in an intramuscular formulation.

The duration of treatment, usually long-term, depends on the progression of the disease. Periodic reassessment of bone resorption parameters is recommended as a guide to determine the need for continuing therapy.

Prevention and treatment of postmenopausal osteoporosis
Dosage may vary according to clinical condition and bone mineral density values as follows:

Madras 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.

Madras 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.

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

When switching from Madras 100 mg + 33 mg injectable solution with lidocaine to Madras 200 mg + 40 mg injectable solution with lidocaine, administration of one vial of Madras 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 Madras 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 the benefits and potential risks, particularly after 5 or more years 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 aged over 65 years, 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 should be used with caution in patients with renal impairment. A dosage reduction of clodronate is recommended as follows:

It is recommended to administer clodronate before haemodialysis, to reduce the dose by 50% on dialysis-free days, and to limit the treatment 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.