Bisfolid

Package leaflet: Information for the patient

BISFOLID 200 mg + 40 mg injection solution

Clodronate disodium – Lidocaine hydrochloride
Generic medicine
Please read this leaflet carefully before 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 effect, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What BISFOLID is and what it is used for
BISFOLID is a medicine containing clodronic acid, an active substance belonging to a group of drugs used to treat bone diseases, called bisphosphonates.
BISFOLID is used in women for the prevention and treatment of bone thinning (osteoporosis) after menopause (the period of permanent cessation of menstrual cycles).

2. What you need to know before using BISFOLID

Do not use BISFOLID:

• 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 BISFOLID.
• If you are allergic to lidocaine or to other amide-type local anesthetics, such as 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 that fails to supply adequate 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. 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 anesthetic lidocaine (see section 3. If you use more BISFOLID than you should).

Warnings and precautions

Talk to your doctor or pharmacist before using BISFOLID.

Before and during treatment, your doctor will ask you to undergo blood tests to monitor kidney and liver function (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 BISFOLID).

In particular, inform your doctor:

• If you have high levels of calcium in the blood.
• If you suffer from kidney disease (renal insufficiency).
• If you are being treated with BISFOLID for cancer or osteoporosis and are undergoing dental treatment or need dental surgery. Also inform your dentist that you are being treated with BISFOLID (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 have had 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 (familial 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 closely monitor you for any possible symptoms.
• If you suffer from respiratory and pulmonary 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 BISFOLID

Inform your doctor or pharmacist if you are currently using, have recently used, or might use any other medicines.

This is particularly important if:

• You are taking other bisphosphonates, medicines used to treat bone diseases, as concomitant use of BISFOLID with other bisphosphonates is contraindicated (see section 2. Do not use BISFOLID).
• You are taking non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to treat inflammation (especially 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 of the stomach wall); fluvoxamine (a medicine used for depression); antiviral medicines such as ritonavir; antibiotics such as macrolide antibiotics (erythromycin) or other antibiotics like ciprofloxacin; antifungal medicines such as ketoconazole, itraconazole, as this may lead to increased blood levels of lidocaine.
• 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 lead to decreased blood levels of lidocaine.
• You are being treated with digitalis, medicines used to treat heart rhythm disorders, as this may increase the risk of heart rhythm disturbances.
• You are taking muscle relaxants used 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, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before using this medicine.

Pregnancy

Avoid using BISFOLID during pregnancy and if you are of childbearing age and 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, breastfeeding should be discontinued during treatment with BISFOLID.

Fertility

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

Driving and using machines

BISFOLID may cause visual disturbances that could affect your ability to drive vehicles or operate machinery.

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

BISFOLID contains sodium

This medicine contains 32 mg of sodium (a main component of table salt) per dose.
This corresponds to 1.6% of the maximum daily dietary intake recommended for an adult.

3. How to use BISFOLID

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 Patient Information Leaflet).
Clodronic acid is primarily eliminated via the kidneys. Therefore, during treatment with clodronic acid, it is necessary to maintain adequate fluid intake.

Method of administration
BISFOLID is 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.
Do not massage the injection site.

If you use more BISFOLID than you should
If you accidentally take an excessive dose of BISFOLID, 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 excitement),
• sedation (physical and mental relaxation),
• loss of sensation in parts of the body (paraesthesia),
• muscle spasms (sudden, involuntary muscle contractions),
• uncontrolled body movements (convulsions),
• reduced blood flow to the body (cardiocirculatory collapse).

Treatment
Your doctor will manage symptoms with appropriate specific therapies.

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

If you stop using BISFOLID
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 gets them.
If you experience any eye or vision problems during treatment, STOP the treatment and consult an ophthalmologist.
Contact 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 in the jaw and/or maxilla), generally associated with tooth extraction and/or local infection (see section 2. Warnings and precautions).

The possible side effects listed below are categorized by frequency:
Common (may affect up to 1 in 10 people):

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

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

• low levels of calcium in the blood with symptoms (symptomatic hypocalcemia),
• increased levels of parathyroid hormone (a hormone regulating calcium levels) in the blood, associated with reduced blood calcium,
• increased levels of alkaline phosphatase in the blood (a test to assess bone and liver health),
• increased levels of transaminases in the blood (a test to assess liver function) more than twice the upper normal limit, without other signs of liver dysfunction,
• 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.

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 symptoms could indicate bone damage in the ear.

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

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

Effects affecting 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 problems.

Effects affecting 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 BISFOLID.

Effects affecting bones and muscles

• severe bone, joint, and muscle pain. Symptoms may appear from days to several months after starting treatment with BISFOLID;
• 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 in the jaw and/or maxilla), generally associated with tooth extraction and/or local infection (see section 2. Warnings and precautions). In most cases, this has occurred in cancer patients.

Effects at the injection site

• tenderness at the injection site, particularly with prolonged treatment duration.

Side effects specific to lidocaine
The following side effects are associated with lidocaine; however, sufficient data are not available 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 low 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 (paresthesia).
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 (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 reduced blood flow (circulatory collapse).
Skin and subcutaneous tissue disorders
Sudden skin redness (various types of skin eruptions), skin rash with itchy bumps (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 or pharmacist. You may also report side effects directly via the national reporting system at 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 BISFOLID

Keep this medicine out of the sight and reach of children.
This medicine does not require any special storage conditions.
Do not use this medicine after the expiry date 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 BISFOLID contains

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

Description of the appearance of BISFOLID and package contents
Injectable solution, clear and colourless, in packs of 3, 6, 9, and 12 vials for intramuscular use.
Marketing Authorisation Holder
Epifarma S.r.l., Via San Rocco 6, 85033 Episcopia (PZ).
Manufacturer
Biomedica Foscama Industria Chimico-farmaceutica S.p.A. - Via Morolense 87 - 03013 Ferentino (FR)
The following information is intended exclusively for physicians or healthcare professionals:
DOSAGE, METHOD AND DURATION OF ADMINISTRATION
The dosage according to clinical condition and mineralometric values may vary as follows:
BISFOLID every 14–28 days for 1 year or longer, depending on the patient's condition.
BISFOLID may be used in patients who have never previously received clodronate treatment.
When switching from administration of clodronate 100 mg + lidocaine 33 mg to BISFOLID 200 mg + 40 mg, administration of one vial of BISFOLID 200 mg + 40 mg every 14 days may be used as an alternative dosing regimen in patients already being treated with one 100 mg vial per week.
Administration of one vial of BISFOLID 200 mg + 40 mg every 28 days may be used as an alternative dosing regimen in patients already being treated with 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 in each individual patient based on potential benefits and 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 over 65 years of age, and no age-specific adverse events have been reported in this age group.
Patients with renal impairment
Clodronate is primarily eliminated via the kidneys. Therefore, it should be used with caution in patients with renal impairment. It is recommended to reduce the clodronate dosage 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 regimen to 5 days. It should be noted that peritoneal dialysis poorly removes clodronate from the circulation.
The solution is incompatible with alkaline solutions or oxidizing solutions.