Clasteon - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Other information Information for healthcare professionals

Active ingredients: Clodronic acid

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine
CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine
CLASTEON 300 mg / 10 ml concentrate for solution for infusion
CLASTEON 400 mg hard capsules

Clasteon package inserts are available for pack sizes:
  • CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with lidocaine 1%, CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with lidocaine 1%, CLASTEON 300 mg / 10 ml concentrate for solution for infusion, CLASTEON 400 mg capsules rigid
  • CLASTEON 300 mg / 10 ml concentrate for solution for infusion
  • CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine, CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine

Indications Why is Clasteon used? What is it for?

CLASTEON is a medicine that contains clodronic acid, an active substance that belongs to a group of medicines for the treatment of bone diseases called bisphosphonates.

CLASTEON is used in adults for the treatment:

  • loss of bone consistency following cancer (tumor osteolysis);
  • bone marrow cancer (multiple myeloma);
  • excessive function of the parathyroid glands (primary hyperparathyroidism).

It is also used in women for the prevention and treatment of bone loss (osteoporosis) after menopause (period of permanent interruption of the menstrual cycle).

Contraindications When Clasteon should not be used

Do not take CLASTEON

  • If you are allergic to clodronic acid or any of the other ingredients of this medicine (listed in section 6).
  • If you are taking other bisphosphonates, medicines similar to CLASTEON.

Precautions for use What you need to know before taking Clasteon

Talk to your doctor or pharmacist before taking CLASTEON.

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

In particular, tell your doctor:

  • If you have high levels of calcium in the blood (hypercalcaemia).
  • If you suffer from kidney disease (kidney failure).
  • If you have severe liver disease.
  • If you are being treated with CLASTEON to treat cancer or osteoporosis, and are undergoing treatment at your dentist or are due to undergo dental surgery. Also tell your dentist that you are being treated with CLASTEON (see section 4. Possible effects unwanted), as preventive dental treatment may be required.
  • If you develop weakness or pain in the thigh, hip or groin during treatment, as this could be an initial symptom of a possible fracture of the femur (see section 4. Possible side effects).
  • If you or someone in your family has or have ever had problems with the esophagus (tube that connects the pharynx to the stomach) which causes delay in the passage of food and stomach emptying, or if you suffer from stomach problems. Your doctor will ask you about pay attention to the administration instructions and watch out for any signs or symptoms that indicate a possible reaction to the esophagus. If you develop symptoms of irritation of the esophagus (eg difficulty in swallowing (dysphagia), pain when swallowing, pain in the back of the mouth or onset / aggravation of heartburn), contact your doctor immediately.
  • If you have difficulty keeping your torso erect for at least 30 minutes from the time you take the capsule.

Children and adolescents

The safety and efficacy of the drug in pediatric patients have not been established.

Interactions Which drugs or foods can modify the effect of Clasteon

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Simultaneous use with other bisphosphonates, medicines used to treat bone diseases, is contraindicated (see section 2. Do not use CLASTEON).

Take care and tell your doctor if:

  • You are taking non-steroidal anti-inflammatory drugs (NSAIDs), medicines used to treat inflammation.
  • You are taking aminoglycosides, medicines used to treat infections.
  • You are taking estramustine, a medicine used to treat prostate cancer (a gland that produces semen in men).
  • If you are taking medicines containing divalent cations (e.g. antacids or iron preparations). In these cases, your doctor will tell you to take CLASTEON 2-3 hours apart.

CLASTEON with food

Tell your doctor or pharmacist if you are taking foods containing divalent cations (e.g. foods containing iron). In these cases, your doctor will tell you to take CLASTEON 2-3 hours apart

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

Avoid taking CLASTEON during pregnancy and if you are of childbearing age and are not using contraceptive therapy (medicines used to prevent pregnancy).

Feeding time

It is not known whether clodronic acid passes into breast milk. Therefore, during treatment with CLASTEON, you should stop breastfeeding.

Fertility

In animal studies, CLASTEON in high doses reduces male fertility. No clinical data on the effect of CLASTEON on human fertility are available.

Driving and using machines

CLASTEON has no effect on the ability to drive and use machines.

CLASTEON contains sodium

CLASTEON 400 mg hard capsules contain 51.31 mg of sodium per capsule.

This should be taken into consideration if you have kidney disease or are on a controlled sodium diet.

Dosage and method of use How to use Clasteon: Dosage

Always take this medicine exactly as your doctor has told you who will tell you the correct dose based on the severity of your disease and the duration of treatment. If in doubt, consult your doctor or pharmacist.

Clodronic acid is eliminated predominantly by the kidney. Therefore, adequate fluid intake should be ensured during treatment with clodronic acid. Dose, method and time of administration (see more detailed information at the end of the Package Leaflet).

Method of administration

Tumor osteolysis. Multiple myeloma. Primary hyperparathyroidism.

Attack phase

For the attack phase, your doctor will give you CLASTEON 300 mg / 10 ml concentrate for solution for infusion. For more information on CLASTEON 300 mg / 10 ml concentrate for solution for infusion see the corresponding Package Leaflet.

Maintenance phase

How much and for how long

The recommended dose is 1-6 capsules per day, divided into 2-3 administrations between meals, for 3-4 weeks.

Your doctor will ask you to repeat these cycles at variable intervals depending on the evolution of the disease and, if necessary, will ask you to undergo tests to assess the health of your bones.

Your doctor will reduce the dose of CLASTEON if you have kidney disease.

Alternatively, your doctor may give you CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine in a muscle.

Prevention and treatment of post menopausal osteoporosis

How much and for how long

The recommended dose is 1 capsule per day for 30 days, followed by 60 days off (for multiple cycles), up to one capsule per day continuously for 1 year or more depending on what your doctor prescribes.

Your doctor will reduce the dose of CLASTEON if you have kidney disease.

Alternatively, your doctor may administer CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine or CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine in a muscle.

How to take the capsules

Take the capsules by mouth with some water and swallow without chewing.

CLASTEON 400 mg capsules should be swallowed whole, preferably in the morning, on an empty stomach with a glass of water. Then do not eat or drink (other than plain water) or take other medicines by mouth for one "hour after". Once you have swallowed the medicine, you should not lie down for 30 minutes.

In the case of several doses per day, the other doses should be taken between meals, at least two hours after and one hour before eating, drinking (if not plain water) or taking other medications by mouth.

Under no circumstances should you take the capsules with milk, food or drugs containing calcium or other divalent cations, as these substances interfere with the absorption of clodronate. Some mineral waters may have a high concentration of calcium and therefore should not be used.

If you forget to take CLASTEON

Do not take a double dose to make up for a forgotten capsule.

If you stop taking CLASTEON

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Clasteon

In case of accidental overdose of CLASTEON contact your doctor or the nearest hospital immediately.

Symptoms of overdose can consist of:

  • low calcium levels in the blood (hypocalcemia)
  • stomach and intestinal disorders
  • high levels of nitrogen in the blood (uremia)
  • liver damage

Symptoms of overdose with high doses of intravenous clodronic acid may include:

  • increased blood creatinine levels
  • kidney disease (kidney dysfunction)

Treatment

The doctor will control the symptoms with specific therapies.

Side Effects What are the side effects of Clasteon

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If during the treatment you develop visual or eye disturbances, STOP the therapy and contact your ophthalmologist.

The possible side effects are listed below according to frequency:

common (may affect up to 1 in 10 people)

  • low blood calcium levels, without symptoms (asymptomatic hypocalcaemia)
  • diarrhea, nausea, vomiting (usually mild in intensity)
  • increased levels of transaminases in the blood (test to evaluate liver function) usually within normal range

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

  • low blood calcium levels, with symptoms (symptomatic hypocalcaemia)
  • increased level of parathyroid hormone (hormone that regulates calcium levels in the blood) associated with reduced blood calcium
  • increased levels of alkaline phosphatase in the blood (test to evaluate the condition of the bones and liver)
  • increased levels of transaminases in the blood (test to evaluate liver function) twice the normal range, with no other abnormalities in liver function
  • allergic reactions that manifest themselves as skin reactions
  • unusual fracture of the femur (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 a first sign of a possible fracture of the femur

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

  • talk to your doctor if you have ear pain, ear discharge and / or ear infection. These episodes could be signs of bone damage in your ear.

In addition, the following side effects may occur, for which the frequency cannot be estimated:

  • effects affecting 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 now been reported with other drugs belonging to the same category of clodronic acid (bisphosphonates)
  • effects affecting the lungs
    • breathing disorders in patients with acetylsalicylic acid-sensitive asthma
    • allergic reactions that manifest themselves as respiratory disorders
  • effects affecting the kidneys and urinary tract
    • kidney disease (kidney failure), severe kidney damage. Rarely, and especially in association with the use of diclofenac (a medicine used to treat inflammation and pain), kidney failure has led to death
  • effects affecting the bones and muscles
    • severe pain in the bones, joints and muscles. The onset of symptoms varies from days to several months after initiation of CLASTEON therapy
    • pain or sore in the mouth or jaw and / or jaw (two bones of the face). These may be the first signs of serious problems (bone death in the jaw and / or jaw), usually associated with tooth extraction and / or local infection (see section 2. Warnings and precautions). In most cases, this has occurred in cancer patients
  • effects affecting the stomach and intestines
    • inflammation or irritation of the esophagus (tube that connects the pharynx to the stomach)
    • inflammation of the stomach (gastritis) - lesions of the esophagus (esophageal ulcers)
    • lesions of the stomach and intestines (gastroduodenal ulcers)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at “www.agenziafarmaco.gov.it/it/responsabili.” By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

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 carton after EXP. The expiry date refers to the last day of that month.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What CLASTEON contains

  • The active ingredient is Disodium clodronate (disodium salt of clodronic acid) 400 mg
  • The other ingredients are Maize starch, magnesium stearate, sodium starch glycolate (type A), talc.

Shell components: gelatin, indigo carmine (E 132), titanium dioxide (E 171).

Description of what CLASTEON looks like and contents of the pack

CLASTEON 400mg hard capsules comes in blister packs of 10 capsules.

Deadline "> Information for healthcare professionals

The following information is intended for medical or healthcare professionals only:

DOSE, METHOD AND TIME OF ADMINISTRATION

Senior citizens

There are no special dosage recommendations of the drug for the elderly. Clinical studies performed included patients over 65 years of age and no specific adverse events were reported for this age group.

Tumor osteolysis. Multiple myeloma. Primary hyperparathyroidism.

The following dosing schedule should be considered indicative and can therefore be adapted to the needs of the individual patient.

Attack phase

In the attack phase, CLASTEON 300 mg / 10 ml concentrate for solution for infusion 300 mg / day in a single slow intravenous administration for 3-8 days is recommended in relation to the trend of clinical and laboratory parameters (calcium, hydroxyprolinuria, etc. .).

For more information on CLASTEON 300 mg / 10 ml concentrate for solution for infusion see the corresponding Summary of Product Characteristics and Package Leaflet.

Maintenance phase

  • CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with lidocaine 1% 100 mg / day intramuscularly for 2-3 weeks

or alternatively

  • CLASTEON 400 mg hard capsules, 1-6 capsules / day, divided into 2-3 administrations between meals, for 3-4 weeks.

These cycles can be repeated at variable intervals according to the evolution of the disease. The periodic evaluation of the bone resorption parameters can usefully guide the therapeutic cycles.

For more information on CLASTEON 300 mg / 10 ml concentrate for solution for infusion and CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with lidocaine see the corresponding Summary of Product Characteristics and Package Leaflet.

Patients with renal insufficiency

Clodronate is mainly eliminated by the kidney. Therefore, it should be used with caution in patients with renal insufficiency. Daily dosages in excess of 1600 mg should not be used continuously.

It is recommended to reduce the Clodronate dosage as follows:

Levels of kidney failure Creatinine clearance, ml / min Dose Mild 50-80 ml / min 1600 mg / day Moderate 30-50 ml / min 1200 mg / day Serious* <30 ml / min 800 mg / day

* For oral clodronate, no pharmacokinetic data are available in patients with renal insufficiency with creatinine clearance less than 10 ml / min. Use in these cases should be avoided, except for short-term treatment in the presence of purely functional renal insufficiency caused by elevated serum calcium levels.

Prevention and treatment of post menopausal osteoporosis.

Depending on the clinical picture and mineralometric values, the dosage may vary as follows:

Oral therapy

CLASTEON 400 mg hard capsules, 1 capsule / day x 30 days, followed by 60 days of suspension (for multiple cycles), up to one capsule / day continuously for 1 year or more depending on the patient's condition.

Alternatively

Parenteral therapy

  • CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with lidocaine 1% intramuscularly 100 mg every 7-14 days, for 1 year or longer depending on the patient's condition.
  • CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with lidocaine 1% intramuscularly 200 mg every 14-28 days, for 1 year or more depending on the patient's condition.

For more information on CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with lidocaine 1% and CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with lidocaine see the corresponding Summary of Product Characteristics and Package Leaflet.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Clasteon can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

CLASTEON

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

CLASTEON 400 mg hard capsules

Each capsule contains

Active principle

Disodium clodronate (disodium salt of clodronic acid) 400 mg

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine

Each vial contains

Active principles

Disodium clodronate (disodium salt of clodronic acid) 100 mg

Lidocaine hydrochloride 33 mg

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine

Each vial contains

Active principles

Disodium clodronate (disodium salt of clodronic acid) 200 mg

Lidocaine hydrochloride 40 mg

CLASTEON 300 mg / 10 ml concentrate for solution for infusion

Each vial contains

Active principle

Disodium clodronate (disodium salt of clodronic acid) 300 mg

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Hard capsules

Solution for injection for intramuscular use

Concentrate for solution for infusion

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Tumor osteolysis. Multiple myeloma. Primary hyperparathyroidism.

Prevention and treatment of post menopausal osteoporosis.

04.2 Posology and method of administration -

Clodronate is eliminated predominantly by the kidney. Therefore, adequate fluid intake should be ensured during treatment with Clodronate.

• Children

The safety and efficacy of the drug in pediatric patients have not been established.

• Senior citizens

There are no special dosage recommendations of the drug for the elderly. Clinical studies performed included patients over 65 years of age and no specific adverse events were reported for this age group.

Tumor osteolysis. Multiple myeloma. Primary hyperparathyroidism.

The following dosing schedule should be considered indicative and can therefore be adapted to the needs of the individual patient.

to) Attack phase

CLASTEON 300 mg / 10 ml concentrate for solution for infusion

300 mg / day in a single dose slow intravenous for 3-8 days in relation to the progress of clinical and laboratory parameters (calcemia, hydroxyprolinuria, etc.).

Clodronate is administered as an intravenous infusion of 300 mg (one 5 ml ampoule) / day diluted in 500 ml of physiological saline (sodium chloride 9 mg / ml) or in a 5% glucose solution (50 mg / ml). This solution should be administered by slow intravenous perfusion over a period of at least two hours.

• Patients with renal insufficiency

It is recommended to reduce the dosage of the clodronate infusion as follows:

Degree of renal insufficiency: Creatinine clearance, ml / min Dosage reduction,% 50-80 25 12-50 25-50 50

It is recommended that 300 mg of clodronate be infused before hemodialysis, that the dose be reduced by 50% on dialysis-free days, and that the treatment schedule be limited to 5 days. Note that peritoneal dialysis removes clodronate poorly. from circulation.

b) Maintenance phase

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine

100 mg / day intramuscularly for 2-3 weeks

or alternatively

CLASTEON 400 mg hard capsules

1-6 capsules / day, divided into 2-3 administrations between meals, for 3-4 weeks.

These cycles can be repeated at variable intervals according to the evolution of the disease. The periodic evaluation of the bone resorption parameters can usefully guide the therapeutic cycles.

CLASTEON 400 mg capsules should be swallowed whole. The first of two to three doses should preferably be taken in the morning on an empty stomach with a glass of water. The patient must, therefore, refrain from eating, drinking (if not plain water) or taking other medications by mouth during the hour following the intake. Once the medicine has been ingested, patients are recommended not to lie down for 30 minutes.

The other doses should be taken between meals, at least two hours after and one hour before eating, drinking (if not plain water) or taking other medications by mouth.

In no case should clodronate be taken with milk, food or drugs containing calcium or other divalent cations, as these substances interfere with the absorption of clodronate. Some mineral waters may have a high concentration of calcium and therefore should not be used.

• Patients with renal insufficiency

Clodronate is mainly eliminated by the kidney. Therefore, it should be used with caution in patients with renal insufficiency. Daily dosages in excess of 1600 mg should not be used continuously.

It is recommended to reduce the Clodronate dosage as follows:

Levels of kidney failure Creatinine clearance, ml / min Dose Mild 50-80 ml / min 1600 mg / day Moderate 30-50 ml / min 1200 mg / day Severe * 800 mg / day * For oral clodronate, no pharmacokinetic data are available in patients with renal insufficiency with creatinine clearance less than 10ml / min. Use in these cases should be avoided, except for short-term treatment in the presence of purely functional renal insufficiency caused by elevated serum calcium levels.

Prevention and treatment of post menopausal osteoporosis.

Depending on the clinical picture and mineralometric values, the dosage may vary as follows:

Oral therapy

From 1 capsule / day x 30 days, followed by 60 days of suspension (for several cycles), up to one capsule / day continuously for 1 year or more depending on the patient's condition.

CLASTEON 400 mg capsules should be swallowed whole. The daily dose should preferably be taken in the morning on an empty stomach with a glass of water. The patient must, therefore, refrain from eating, drinking (if not plain water) or taking other medications by mouth during the hour following the intake. Once the medicine has been ingested, patients are recommended not to lie down for 30 minutes.

In no case should clodronate be taken with milk, food or drugs containing calcium or other divalent cations, as these substances interfere with the absorption of clodronate. Some mineral waters may have a high concentration of calcium and therefore should not be used.

Parenteral therapy

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine

intramuscularly 100 mg every 7-14 days, for 1 year or more depending on the patient's condition.

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine

intramuscularly 200 mg every 14-28 days, for 1 year or more depending on the patient's condition.

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine can be used in patients who have never started treatment with clodronate.

In case of switching from administration of CLASTEON 100 mg / 3.3 ml to CLASTEON 200 mg / 4 ml, administration of one ampoule of CLASTEON 200 mg / 4 ml every 14 days can be used as an alternative dosing regimen in patients already on treatment. with one 100 mg vial per week.

Administration of one vial of CLASTEON 200 mg / 4 ml every 28 days can be used as an alternative dosing regimen in patients already being treated with a 100 mg vial every two weeks.

• Patients with renal insufficiency

It is recommended to reduce the clodronate dosage as follows:

Degree of renal insufficiency: Creatinine clearance, ml / min Dosage reduction,% 50-80 25 12-50 25-50 50

It is recommended to administer clodronate prior to hemodialysis, reduce the dose by 50% on dialysis-free days, and limit the treatment schedule to 5 days. Note that peritoneal dialysis removes clodronate poorly from the circulation.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be reassessed in each individual patient periodically based on the potential benefits and risks, particularly after 5 or more years of use.

CLASTEON 300 mg / 10 ml concentrate for solution for infusion

This medicine is for intravenous use only .

Dilute before administration.

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine

These medicines are for intramuscular use only .

To avoid accidental intravascular injection it is recommended to aspirate before injecting the medicine.

Avoid massaging the injection site.

04.3 Contraindications -

Hypersensitivity to the active substance (clodronic acid) or to excipients. Concurrent treatments with other bisphosphonates.

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine

Specific contraindications of lidocaine

• hypersensitivity to lidocaine or other local anesthetics of the amide type (for example: bupivacaine, mepivacaine, ropivacaine, levobupivacaine);

• Adam-Stokes syndrome, Wolff-Parkinson White syndrome (atrial fibrillation) or severe degrees of sino-atrial, atrioventricular or intraventricular block, acute heart failure.

04.4 Special warnings and appropriate precautions for use -

Adequate fluid intake should be maintained during treatment with clodronate. This is particularly important when clodronate is administered intravenously and in patients with hypercalcaemia or renal insufficiency.

Renal function should be monitored before and during treatment by serum creatinine, calcium and phosphate levels.

In clinical studies, asymptomatic and reversible elevations in transaminases occurred, with no changes in other liver function tests. Monitoring of transaminases is recommended (see also section 4.8).

Clodronate should be used with caution in patients with renal insufficiency (see section 4.2 Posology and method of administration).

Intravenous administration of significantly higher than recommended doses can cause severe kidney damage, especially if the infusion rate is too high.

Oral bisphosphonates have been associated with esophagitis, gastritis, esophageal ulcers and gastroduodenal ulcers.

Therefore, caution should be exercised:

• in patients with a history of esophageal disorders causing delayed esophageal transit and gastric emptying, such as narrowing or achalasia,

• in patients unable to keep their torso erect for at least 30 minutes after taking the capsule,

• if the medicine is given to patients with current or recent problems in the esophagus or upper gastrointestinal tract. Physicians should emphasize to the patient the importance of heeding the administration instructions and of the appearance of any signs or symptoms that indicate a possible oesophageal reaction. Patients should be advised that if they develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing, retrosternal pain or onset / aggravation of heartburn, you should seek medical attention promptly.

Osteonecrosis of the jaw, usually associated with tooth extraction and / or local infection (including osteomyelitis), has been reported in cancer patients receiving regimens including both intravenous and oral bisphosphonates. Many of these patients were also treated with chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis being treated with oral bisphosphonates.

Before starting bisphosphonate treatment in patients with concomitant risk factors (such as cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene) the need for a dental examination with appropriate preventive dental procedures should be considered and, during treatment, these patients should, if possible, avoid invasive dental procedures. In patients who have developed osteonecrosis of the jaw during bisphosphonate therapy, dental surgery can exacerbate the condition. For patients requiring dental surgery, there are no data available to suggest that discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.

The clinical judgment of the physician must guide the management program of each patient, based on the individual assessment of the risk / benefit ratio.

Osteonecrosis of the external auditory canal has been reported in conjunction with the use of bisphosphonates, predominantly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include the use of steroids and chemotherapy and / or local risk factors such as infection or trauma. Osteonecrosis of the external auditory canal should be considered in patients treated with bisphosphonates who have ear symptoms, including chronic ear infections.

Atypical fractures of the femur

Atypical subtrochanteric and shaft fractures of the femur have been reported, mainly in patients on long-term bisphosphonate therapy for osteoporosis. These short transverse or oblique fractures can occur anywhere in the femur from just below the lesser trochanter to above the supracondylar line. These fractures occur spontaneously or after minimal trauma and some patients experience thigh or groin pain, often associated with imaging findings and radiographic evidence of stress fractures, weeks or months before the onset of stress fractures. a complete femoral fracture. Fractures are often bilateral; therefore in bisphosphonate-treated patients who have sustained a femoral shaft fracture, the contralateral femur should be examined. Limited healing of these fractures has also been reported. In patients with suspected atypical femoral fracture, consideration should be given to discontinuing bisphosphonate therapy pending an assessment of the patient based on the individual benefit-risk ratio.

During treatment with bisphosphonates, patients should be advised to report any pain in the thigh, hip or groin and any patient who exhibits such symptoms should be evaluated for the presence of an incomplete fracture of the femur.

Important warnings about some excipients :

CLASTEON 400 mg hard capsules contains 51.31 mg of sodium per capsule.

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine contains 17.02 mg of sodium per dose.

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine contains 32.92 mg of sodium per dose.

CLASTEON 300 mg / 10 ml concentrate for solution for infusion contains 49.14 mg of sodium per dose.

This should be taken into consideration for administration to patients with impaired renal function or on a low sodium diet.

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine

Lidocaine Specific Warnings and Precautions

Accidental intravascular injection increases the risk of toxic effects due to lidocaine.

The toxic effects associated with local anesthetics are often caused by too high plasma concentrations; therefore a careful surveillance is necessary for the recognition of toxic effects at least in the first 30 minutes after administration.Somnolence is the first sign of an elevated plasma rate; other effects include feelings of intoxication followed by sedation, paraesthesia and fasciculations; seizures may occur in severe reactions. With intravenous injection, seizures and cardiovascular collapse can occur very quickly.

The utmost attention must be paid to avoid accidental intravascular administration.

A careful evaluation of the risk / benefit ratio and a more accurate control of the patient are required in the presence of:

• heart disease, in particular bradyarrhythmias and heart failure: increased risk of lidocaine toxicity;

• severe liver disease: increased risk of lidocaine toxicity;

• familial malignant hyperthermia: a crisis can also be triggered by local anesthetics such as lidocaine.

04.5 Interactions with other medicinal products and other forms of interaction -

Concomitant use with other bisphosphonates is contraindicated.

The concomitant use of clodronate with non-steroidal anti-inflammatory drugs (NSAIDs), most often with diclofenac, has been associated with renal dysfunction.

Due to the "increased risk of" hypocalcaemia, caution should be used when co-administering clodronate with aminoglycosides.

Concomitant use of estramustine phosphate with clodronate has been reported to increase the serum concentration of estramustine phosphate up to a maximum of 80%.

Clodronate forms complexes with divalent cations which are poorly soluble in water. Therefore, clodronate should not be administered intravenously with solutions containing divalent cations (e.g. Ringer's solution). Also, clodronate hard capsules should not be taken with foods or drugs containing divalent cations (e.g. antacids or iron preparations). The assumption must be carried out after 2-3 hours.

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine

Specific interactions of lidocaine

Propranolol prolongs the plasma half-life of lidocaine. Cimetidine may cause increased levels of lidocaine in the blood. Lidocaine administration in patients receiving digitalis may increase the risk of bradycardia and atrioventricular conduction disturbances

04.6 Pregnancy and breastfeeding -

Fertility

In animal studies, clodronate does not cause fetal harm, but large doses reduce male fertility.

No clinical data on the effect of clodronate on human fertility are available. For the use of clodronate in pregnancy and lactation, see sections 4.6.2 and 4.6.3.

Pregnancy

Although clodronate passes through the placental barrier in animals, it is not known in humans whether it passes into the fetus. Furthermore, it is not known whether clodronate can cause fetal harm or affect reproductive function in humans. There is only a limited amount of data on the use of clodronate in pregnant women. CLASTEON is not recommended during pregnancy and in women of childbearing potential not protected by effective contraceptive therapy.

Feeding time

In humans, it is not known whether clodronate is excreted in human milk. A risk to the suckling child cannot be excluded. Therefore, breastfeeding should be discontinued during treatment with CLASTEON.

04.7 Effects on ability to drive and use machines -

The drug has no effect on the ability to drive and use machines.

04.8 Undesirable effects -

The use of high oral doses can give rise to gastrointestinal disturbances.

Intramuscular administration of clodronate may induce tenderness at the injection site, also in consideration of the duration of therapy.

In rare circumstances bisphosphonates (including clodronate) have been associated with visual and ocular disturbances. In case of such disturbances it is necessary to stop the treatment and refer to an ophthalmologist.

Osteonecrosis of the mandible and / or maxilla, generally associated with tooth extraction and / or local infection, has been reported in cancer patients treated with regimens including bisphosphonates administered mainly intravenously (see also section 4.4).

The most commonly reported reaction is diarrhea, which is usually mild and is more frequent with higher dosages.

These adverse reactions can occur with both oral and parenteral treatment, although their frequency may differ.

Organic system classification Common ≥ 1/100 to Rare ≥ 1 / 10,000 y Metabolism and nutrition disorders Asymptomatic hypocalcemia Symptomatic hypocalcaemia, Increased serum parathyroid hormone associated with decreased serum calcium, Increased serum alkaline phosphatase * Gastrointestinal disorders Diarrhea **, Nausea **, Vomiting ** Hepatobiliary disorders Increased transaminases, usually within the normal range. Increase in transaminases twice the normal range, with no other abnormalities in liver function. Skin and subcutaneous tissue disorders Hypersensitivity reactions which manifest themselves as skin reactions * In patients with metastases, they may also be due to hepatic or bone involvement. ** Usually mild The more appropriate MedDRA term is used to describe a reaction, its synonyms and related conditions.

Post-marketing experience

• Eye disorders

Cases of uveitis have been reported during post-marketing experience with clodronate. The following reactions have been reported with other bisphosphonates: conjunctivitis, episcleritis and scleritis. Conjunctivitis was only reported with clodronate in a patient receiving concomitant treatment with another bisphosphonate. So far, episcleritis and scleritis have not been reported with clodronate (bisphosphonate class adverse reaction).

• Respiratory, thoracic and mediastinal disorders.

Impaired respiratory function in patients with aspirin-sensitive asthma. Hypersensitivity reactions manifesting as respiratory disturbances.

• Renal and urinary disorders

Renal insufficiency (increased serum creatinine and proteinuria), severe renal impairment especially after rapid intravenous infusion of high doses of clodronate (for instructions on posology see section 4.2 Posology and method of administration "Patients with renal insufficiency"). Individual cases of renal failure, rarely with fatal outcome, have been reported especially with concomitant use of NSAIDs, most often diclofenac.

• Musculoskeletal and connective tissue disorders

There have been isolated reports of osteonecrosis of the jaw, primarily in patients who had previously been treated with amino bisphosphonates such as zoledronate and pamidronate (see also section 4.4). Severe bone, joint and / or muscle pain has been reported in patients taking CLASTEON. However, such reports have been infrequent and, in randomized placebo-controlled trials, there is no difference between patients treated with placebo or CLASTEON. The onset of symptoms varies from days to several months after initiation of CLASTEON therapy.

The following reactions have been reported during post-marketing experience (frequency rare): Atypical subtrochanteric and diaphyseal fractures of the femur (bisphosphonate class adverse reaction).

Very rare: osteonecrosis of the external auditory canal (adverse reaction for the bisphosphonate class).

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine

Side effects specific to lidocaine

Undesirable effects that occur with lidocaine are usually due to either hypersensitivity reactions or excessively high blood concentrations due to accidental intravascular injection and / or overdosing. The resulting systemic toxicity may underlie occasional central nervous system excitatory effects and occasional cardiovascular depressive effects.

To see Lidocaine Specific Warnings and Precautions in section 4.4

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose -

• Symptoms

Increased serum creatinine and renal dysfunction have been reported with high doses of clodronate administered intravenously. One case of uremia and liver damage has been reported following the accidental ingestion of 20,000 mg (50X400 mg) of clodronate.

• Treatment

Treatment of overdose should be symptomatic. Adequate hydration should be ensured, and renal function and serum calcium monitored.

Although there is no experience of overdose with clodronic acid, it is however theoretically possible that high quantities of the product may induce hypocalcemia. In such cases, treatment should consist in correcting the hypocalcemia by means of an adequate dietary supplement or, in severe cases, by administration intravenous calcium.

Should alterations in renal function occur due to the formation of calcium aggregates, therapy must aim at restoring the function itself.

For the effects of lidocaine overdose see Lidocaine Specific Warnings and Precautions in section 4.4.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: drugs that affect bone structure and mineralization.

ATC code: M05BA02.

Clodronic acid

Clodronic acid belongs to the category of diphosphonates, drugs capable of inhibiting the formation and dissolution of hydroxyapatite crystals. Pharmacological and clinical investigations have shown the remarkable inhibitory effect of clodronic acid on bone resorption, consequent to the inhibition of activity. osteoclasty, in all experimental and clinical conditions in which this is exaggeratedly increased. These conditions include neoplastic diseases such as bone metastases and multiple myeloma, endocrinopathies such as primary hyperparathyroidism, as well as metabolic osteopathies such as osteopenia due to immobilization and, in particular, post menopausal osteoporosis.

The efficacy of clodronic acid in the treatment of hypercalcemic episodes was also of particular importance.

Recent research has demonstrated the efficacy of the drug in reducing skeletal morbidity secondary to malignant neoplasms, in particular breast cancer.

Finally, the analgesic effect of the drug in the treatment of pain secondary to bone metastases, an effect that is established from the first days of intravenous treatment, is also relevant.

Prolonged use of the drug does not induce bone mineralization defects, as confirmed by biopsy investigations.

Lidocaine

Pharmacotherapeutic group: local anesthetics - ATC: N01BB02.

05.2 "Pharmacokinetic properties -

Clodronic acid

The absorption of clodronic acid after oral administration is very low, in humans it is of the order of 2%. Disodiodichloromethylenediphosphonate is rapidly cleared from the body; 90% of the absorbed dose is found in the urine in an unmetabolized form in the first 24 hours after administration.

Lidocaine

Lidocaine peaks on average within 15-20 minutes of administration; it is distributed in the fluids and tissues of the organism and the half-life is about 2 hours; is metabolised in the liver and is excreted predominantly by the kidney, both as such and as a metabolite

05.3 Preclinical safety data -

The acute toxicity of disodiodichloromethylenediphosphonate was found to be remarkably low. Rat: LD50 1700 mg / kg / os; 430 mg / kg i.p .; 65 mg / kg i.v.

Chronic toxicity: per os in rats, up to 200 mg / kg / day for over 6 months, no toxic effect; per os in the dog, up to 40 mg / kg / day for over 6 months, no toxic effect.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

CLASTEON 400 mg hard capsules

Sodium starch glycolate (type A), corn starch, talc, magnesium stearate.

Components of the enclosure

Gelatin, titanium dioxide (E171), indigo carmine (E132).

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine

sodium bicarbonate, water for injections.

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine

sodium bicarbonate, water for injections.

CLASTEON 300 mg / 10 ml concentrate for solution for infusion

sodium bicarbonate, water for injections.

06.2 Incompatibility "-

CLASTEON 400 mg hard capsules

Not relevant.

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine

CLASTEON 300 mg / 10 ml concentrate for solution for infusion

Solution for injection for intramuscular use and concentrate for solution for infusion: incompatible with alkaline solutions or oxidizing solutions.

06.3 Period of validity "-

CLASTEON 400 mg hard capsules: 5 years.

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine: 3 years.

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine: 2 years.

CLASTEON 300 mg / 10 ml concentrate for solution for infusion: 3 years.

06.4 Special precautions for storage -

This medicinal product does not require any special storage conditions

06.5 Nature of the immediate packaging and contents of the package -

CLASTEON 400 mg hard capsules: 1 PVC / PVDC aluminum blister 10 capsules

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine: 6-12 100 mg vials in colorless neutral glass

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine: 3-6 200 mg vials in colorless neutral glass

CLASTEON 300 mg / 10 ml concentrate for solution for infusion: 6-12 vials 300 mg in colorless neutral glass

06.6 Instructions for use and handling -

No special instructions.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

ABIOGEN PHARMA S.p.A. - Via Meucci 36 - Loc. Ospedaletto - PISA.

08.0 MARKETING AUTHORIZATION NUMBER -

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine, 6 ampoules

AIC n. 026372072

CLASTEON 100 mg / 3.3 ml solution for injection for intramuscular use with 1% lidocaine, 12 ampoules

AIC n. 026372084

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine, 3 ampoules

AIC n. 026372096

CLASTEON 200 mg / 4 ml solution for injection for intramuscular use with 1% lidocaine, 6 ampoules

AIC n. 026372108

CLASTEON 300 mg / 10 ml concentrate for solution for infusion, 6 ampoules

AIC n. 026372033

CLASTEON 300 mg / 10 ml concentrate for solution for infusion, 12 ampoules

AIC n. 026372045

CLASTEON 400 mg hard capsules, 10 capsules

AIC n. 026372058

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Date of first authorization: July 1987

Latest renewal date: October 2016

10.0 DATE OF REVISION OF THE TEXT -

February 2016

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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