Zometa - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Zoledronic acid

Zometa 4 mg powder and solvent for solution for infusion

Why is Zometa used? What is it for?

The active ingredient in Zometa is zoledronic acid, which belongs to a group of substances called bisphosphonates. Zoledronic acid works by binding to the bone and slowing down the rate of metabolism. It is used:

  • To prevent bone complications, such as fractures, in adult patients with bone metastases (spread of the tumor from the primary tumor site to the bone).
  • To reduce the amount of calcium in the blood in adult patients where it is too high due to the presence of a tumor. Tumors can accelerate normal bone metabolism so that the release of calcium from the bone is increased. This condition is known as neoplastic hypercalcemia (TIH).

Contraindications When Zometa should not be used

Carefully follow all instructions given to you by your doctor.

Before starting treatment with Zometa, your doctor will carry out blood tests and check your response to treatment at regular intervals.

Zometa should not be given to you:

  • if you are breastfeeding.
  • if you are allergic to zoledronic acid, another bisphosphonate (the group of substances to which Zometa belongs) or any of the other ingredients of this medicine

Precautions for use What you need to know before taking Zometa

Talk to your doctor before you are given Zometa:

  • if you have or have ever had kidney problems.
  • if you have or have had pain, swelling or numbness in the jaw or a feeling of heaviness in the jaw or loosening of a tooth. Your doctor may recommend that you undergo a dental examination before starting treatment with Zometa.
  • if you are having dental treatments or are due to undergo dental surgery, please inform your dentist that you are being treated with Zometa and tell your doctor about your dental treatments.

During treatment with Zometa, you must maintain good oral hygiene (which includes regular teeth brushing) and receive routine dental check-ups. Tell your doctor and dentist immediately if you experience any problems with your mouth or teeth such as loosening, pain, swelling or non-healing sores or discharge, as these may be signs of a condition called osteonecrosis of the jaw.

Patients on chemotherapy and / or radiotherapy, who are taking steroids, who are undergoing dental surgery, who do not receive routine dental care, who have gum disease, who are smokers, or who have previously been treated with bisphosphonates (used to treat or prevent bone disease) have a higher risk of developing osteonecrosis of the jaw.

Reduced blood calcium levels (hypocalcaemia), which can sometimes cause muscle cramps, dry skin, burning sensation, have been reported in patients treated with Zometa. Cases of irregular heartbeat (cardiac arrhythmia), convulsions, spasms and muscle contractions (tetany) secondary to severe hypocalcaemia have been reported. In some circumstances hypocalcaemia can be life threatening. If any of these apply to you, tell your doctor immediately. If there is a pre-existing hypocalcaemia condition, it must be treated before starting the first dose of Zometa. You will be given an adequate calcium and vitamin D supplement.

Patients aged 65 and over

Zometa can be given to people aged 65 and over. There is no evidence that additional precautions are necessary.

Children and adolescents

Zometa is not recommended for use in adolescents and children under the age of 18.

Interactions Which drugs or foods may change the effect of Zometa

Tell your doctor if you are taking, have recently taken or might take any other medicines. It is especially important to tell your doctor if you are also taking:

  • Aminoglycosides (medicines used to treat severe infections), calcitonin (a type of medicine used to treat postmenopausal osteoporosis and hypercalcaemia), loop diuretics (a type of medicine used to treat high blood pressure or edema) or other medicines that lower calcium levels, as the combination of these substances with bisphosphonates may cause a large decrease in the concentration of calcium in the blood.
  • Thalidomide (a medicine used to treat certain types of blood cancers involving the bones) or any other medicine that may be harmful to the kidneys.
  • Aclasta (a medicine which always contains zoledronic acid and which is used to treat osteoporosis and other non-cancer bone diseases), or any other bisphosphonates, as the combined effects of these medicines when taken together with Zometa are not known .
  • Anti-angiogenic medicines (used to treat cancer), as the combination of these with Zometa has been associated with an increased risk of osteonecrosis of the jaw

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant, you should not be given Zometa. Tell your doctor if you are pregnant or suspect pregnancy.

If you are breastfeeding, you should not be given Zometa.

Ask your doctor for advice before taking any medicine during pregnancy or if you are breastfeeding.

Driving and using machines

There have been very rarely cases of drowsiness and drowsiness with the use of Zometa. You should therefore exercise extreme caution when driving, operating machinery or performing other activities that require your full attention.

Dose, Method and Time of Administration How to use Zometa: Posology

  • Zometa should only be administered by healthcare professionals trained in the use of bisphosphonates intravenously, ie through a vein.
  • Your doctor will recommend that you drink enough water before each treatment to help prevent dehydration.
  • Carefully follow all other instructions given by your doctor, pharmacist or nurse.

How much is administered

  • The usual single dose is 4 mg.
  • If you have kidney problems, your doctor will give you a reduced dose based on the severity of the kidney problem.

How often is Zometa administered

  • If you are being treated for the prevention of bone complications caused by bone metastases, you will be given an infusion of Zometa every three to four weeks.
  • If you are being treated to reduce the amount of calcium in your blood, you will normally only be given one infusion of Zometa.

How Zometa is given

  • Zometa is administered into a vein as an infusion lasting at least 15 minutes and should be administered as a single intravenous solution in a separate infusion line.

Patients whose blood levels of calcium are not too high will also be prescribed calcium and vitamin D supplements, to be taken every day.

Overdose What to do if you have taken too much Zometa

If you have been given doses higher than those recommended, you should be carefully monitored by your doctor. This is because you may develop serum electrolyte abnormalities (e.g. abnormal levels of calcium, phosphorus and magnesium) and / or changes in kidney function, including severe renal impairment. If your calcium levels drop too low, you may need to give you calcium supplementation by infusion.

Side Effects What are the side effects of Zometa

Like all medicines, this medicine can cause side effects, although not everybody gets them. The most common are usually mild and will likely disappear in a short time.

Tell your doctor if any of the following serious side effects occur:

Common (may affect up to 1 in 10 patients):

  • Severe kidney failure (this will be ascertained by your doctor through some specific blood tests).
  • Low levels of calcium in the blood.

Uncommon (may affect up to 1 in 100 patients):

  • Pain in the mouth, teeth and / or jaw, swelling or non-healing of sores inside the mouth or jaw, discharge, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. be signs of a lesion of the jaw (osteonecrosis). If you experience such symptoms during or after stopping treatment with Zometa, please inform your doctor and dentist immediately.
  • An irregular heart rhythm (atrial fibrillation) has been observed in patients being treated with zoledronic acid for postmenopausal osteoporosis. It is currently unknown whether zoledronic acid causes this irregular heart rhythm, but you should tell your doctor if you get these symptoms after you she was given zoledronic acid.
  • Severe allergic reactions: shortness of breath, swelling especially of the face and throat.

Rare (may affect up to 1 in 1,000 patients):

  • As a consequence of low calcium levels: irregular heartbeat (cardiac arrhythmia secondary to hypocalcemia).

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

  • As a consequence of low calcium levels: convulsions, numbness and tetany (secondary to hypocalcemia).

Tell your doctor as soon as possible if any of the following side effects occur:

Very common (may affect more than 1 in 10 patients):

  • Low levels of phosphates in the blood.

Common (may affect up to 1 in 10 patients):

  • Headache and a flu-like syndrome with fever, fatigue, weakness, sleepiness, chills, and aches in the bones, joints and / or muscles. In most cases, no specific treatment is required and the symptoms disappear after a short time (a couple of hours or days).
  • Gastrointestinal reactions, such as nausea and vomiting, as well as loss of appetite.
  • Conjunctivitis.
  • Low levels of red blood cells (anemia).

Uncommon (may affect up to 1 in 100 patients):

  • Hypersensitivity reactions.
  • Low blood pressure.
  • Chest pain.
  • Skin reactions (redness and swelling) at the infusion site, rash, itching.
  • High blood pressure, shortness of breath, dizziness, anxiety, sleep disturbances, taste disturbances, tremor, tingling or numbness of the hands or feet, diarrhea, constipation, abdominal pain, dry mouth.
  • Low levels of white blood cells and platelets in the blood.
  • Low levels of magnesium and potassium in the blood. The doctor will monitor them and take the necessary measures.
  • Weight gain.
  • Increased sweating.
  • Drowsiness.
  • Blurred vision, eye damage, sensitivity to light
  • Sudden chills with fainting, weakness or collapse.
  • Difficulty in breathing with wheezing or coughing.
  • Urticaria.

Rare (may affect up to 1 in 1,000 patients):

  • Slow heartbeat.
  • Confusion.
  • Rarely, an unusual fracture of the femur may occur particularly in patients on long-term treatment for osteoporosis. Contact your doctor if you experience pain, weakness or discomfort in the thigh, hip or groin as this may be an early indication. of a possible fracture of the femur.
  • Interstitial lung disease (inflammation of the lung tissue).
  • Flu-like symptoms which include arthritis and joint swelling.
  • Painful redness and / or swelling of the eyes.

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

  • Fainting due to low blood pressure.
  • Severe pain in the bones, joints and / or muscles, occasionally disabling.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Your doctor, pharmacist or nurse know how to store Zometa properly (see section 6).

What Zometa contains

  • The active substance in Zometa is zoledronic acid. One vial contains 4 mg of zoledronic acid, corresponding to 4.264 mg of zoledronic acid monohydrate.
  • The other ingredients are: mannitol, sodium citrate.

What Zometa looks like and contents of the pack

Zometa is supplied as a powder in a vial. One vial contains 4 mg of zoledronic acid.

Each pack contains the vial of powder with a 5 ml ampoule of water for injections to be used for dissolving the powder.

Zometa is supplied in single packs containing 1 or 40 vials and 1 or 4 ampoules respectively and as multipacks containing 10 (10x 1 + 1) vials and ampoules.

Not all pack sizes may be marketed.

INFORMATION FOR HEALTHCARE STAFF

How to prepare and administer Zometa

  • To prepare a solution for infusion containing 4 mg of zoledronic acid, add, in sterile conditions, 5 ml of water for injections, using the special vial included in the product package, to the vial containing the Zometa powder. Shake the vial gently. to dissolve the powder.
  • Further dilute the reconstituted Zometa solution (5 ml) with 100 ml of calcium-free or other divalent cation-free solution for infusion. If a reduced dose of Zometa is required, initially withdraw the appropriate volume of reconstituted solution (4 mg / 5 ml) as indicated below and then further dilute it in 100 ml of solution for infusion. To avoid potential incompatibilities, the infusion solution used for dilution should be 0.9% w / v saline or 5% w / v glucose solution.

The reconstituted Zometa solution must not be mixed with solutions containing calcium or other divalent cations such as lactated Ringer's solution.

Instruction for the preparation of Zometa in reduced dosages:

Withdraw the appropriate volume of the reconstituted solution (4 mg / 5 ml), as follows:

  • 4.4 ml for the 3.5 mg dose
  • 4.1 ml for the 3.3 mg dose
  • 3.8 ml for the 3.0 mg dose
  • For single use only.

Any remaining unused solution should be discarded. Only the clear solution, free from visible particles and colorless, should be used. Aseptic techniques must be followed during the preparation of the infusion.

  • From a microbiological point of view, the reconstituted and diluted solution for infusion should be used immediately after first opening. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 ° C - 8 ° C. The refrigerated solution should be returned. at room temperature before administration.
  • The solution containing zoledronic acid should be administered as a single infusion lasting 15 minutes in a separate infusion line. Patients' hydration status should be assessed before and after administration of Zometa to ensure they are adequately hydrated.
  • Studies performed on different infusion lines consisting of polyvinyl chloride, polyethylene and polypropylene have not shown incompatibility with Zometa.
  • As there are no data on the compatibility of Zometa with other intravenously administered substances, Zometa must not be mixed with other medicinal products and / or substances and must always be administered via a separate infusion line.

How to store Zometa

  • Keep Zometa out of the sight and reach of children.
  • Do not use Zometa after the expiry date which is stated on the pack.
  • The closed vial does not require any special storage conditions.
  • The diluted Zometa solution for infusion should be used immediately to avoid microbiological contamination.

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 Zometa 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 interaction04.6 Pregnancy and lactation Pregnancy04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE DE THE FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIATION DRUGS, FURTHER DETAILED INSTRUCTIONS ON QUALITY PREPARATION

01.0 NAME OF THE MEDICINAL PRODUCT

ZOMETA 4 MG POWDER AND SOLVENT FOR SOLUTION FOR INFUSION

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains 4 mg of zoledronic acid, corresponding to 4.264 mg of zoledronic acid monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Powder and solvent for solution for infusion

White to off-white and clear powder, colorless solvent.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

• Prevention of skeletal related events (pathological fractures, vertebral crushing, radiotherapy or bone surgery, neoplastic hypercalcemia) in adult patients with advanced malignant tumors affecting the bone.

• Treatment of adult patients with neoplastic hypercalcaemia (TIH).

04.2 Posology and method of administration

Zometa should only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates. Patients treated with Zometa should be given the package leaflet and the patient reminder card.

Dosage

Prevention of skeletal related events in patients with advanced malignant tumors affecting the bone

Adults and elderly people

The recommended dose in the prevention of skeletal related events in patients with advanced malignancies affecting the bone is 4 mg zoledronic acid every 3 to 4 weeks.

Patients should also be given a supplement of 500 mg / day of oral calcium and 400 IU / day of vitamin D.

The decision to treat patients with bone metastases for the prevention of related skeletal events must take into account that the treatment effect is manifested in 2-3 months.

Treatment of TIH

Adults and elderly people

The recommended dose in hypercalcaemia (albumin corrected calcium ≥ 12.0 mg / dL or 3.0 mmol / L) is a single dose of 4 mg zoledronic acid.

Patients with renal impairment

TIH:

In TIH patients who also have severe renal impairment, treatment with Zometa should only be considered after evaluation of the risks and benefits of the treatment. In clinical trials, patients with serum creatinine> 400 μmol / L or> 4.5 mg / dL were excluded. No dose adjustment is necessary in TIH patients with serum creatinine values

Prevention of skeletal related events in patients with advanced malignant tumors:

Serum creatinine and creatinine clearance (CLcr) should be determined before initiating treatment with Zometa in patients with multiple myeloma or bone metastases from solid tumors. CLcr is calculated from serum creatinine using the Cockcroft-Gault formula. Zometa is not recommended for patients presenting with severe renal impairment prior to initiation of therapy, defined for this population as CLcr 265 μmol / l or> 3.0 mg / dl.

In patients with bone metastases with mild to moderate renal impairment, defined for this population as CLcr 30-60 ml / min, the following dosage of Zometa is recommended (see also section 4.4):


Baseline Creatinine Clearance (mL / min) Recommended Zometa dosage * > 60 4.0 mg of zoledronic acid 50-60 3.5 mg * of zoledronic acid 40-49 3.3 mg * of zoledronic acid 30-39 3.0 mg * of zoledronic acid

* Doses were calculated assuming a target AUC of 0.66 (mg • hr / L) (CLcr = 75 mL / min). With administration of the reduced dose in patients with renal impairment an AUC value equal to that observed in patients with creatinine clearance of 75 ml / min is expected to be achieved.

After initiation of therapy, serum creatinine should be determined prior to each administration of Zometa and, in the event of worsening of renal function, treatment should be discontinued. In clinical trials, worsening of renal function was defined as follows reported:

- For patients with normal baseline serum creatinine values ​​(

• For patients with abnormal baseline serum creatinine values ​​(> 1.4 mg / dL or> 124 μmol / L), an increase of 1.0 mg / dL or 88 μmol / L.

In clinical studies, Zometa treatment was resumed only when creatinine returned to within 10% of baseline (see section 4.4). Treatment with Zometa should be resumed at the same strength as was used prior to stopping treatment.

Pediatric population

The safety and efficacy of zoledronic acid in children aged 1 year to 17 years have not been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.

Method of administration

Intravenous use.

Zometa 4 mg powder and solvent for solution for infusion, reconstituted and subsequently diluted to 100 ml (see section 6.6), should be administered as a single intravenous infusion over not less than 15 minutes.

In patients with mild or moderate renal impairment, a reduction in the dose of Zometa is recommended (see section "Posology" above and section 4.4).

Instructions for preparing Zometa in reduced dosages

Withdraw as needed an appropriate volume of the reconstituted solution (4 mg / 5 ml):

- 4.4 ml for the 3.5 mg dose

- 4.1 ml for the 3.3 mg dose

• 3.8 ml for the 3.0 mg dose

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6. The withdrawn quantity of the reconstituted solution must be diluted in 100 ml of sterile 0.9% w / v saline solution or 5% w / v glucose solution. The dose should be administered as a single intravenous infusion lasting not less than 15 minutes.

The reconstituted solution of Zometa must not be mixed with solutions for infusion containing calcium or other divalent cations such as lactated Ringer's solution, and must be administered as a single intravenous solution in a separate infusion line.

Patients should be kept well hydrated before and after administration of Zometa.

04.3 Contraindications

• Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients listed in section 6.1

• Breastfeeding (see section 4.6)

04.4 Special warnings and appropriate precautions for use

General

Prior to administration of Zometa, patients should be carefully evaluated to ensure they are adequately hydrated.

Excessive hydration should be avoided in patients at risk for heart failure.

During therapy with Zometa, normal metabolic parameters related to hypercalcaemia, such as serum calcium, phosphate and magnesium levels, should be closely monitored. If hypocalcaemia, hypophosphataemia or hypomagnesaemia occur, short-term supplementary therapy may be required. patients with untreated hypercalcaemia generally have some degree of renal impairment, therefore careful monitoring of renal function should be considered.

Zometa contains the same active substance as Aclasta (zoledronic acid). Patients being treated with Zometa should not be treated concurrently with Aclasta or any other bisphosphonate, as the combined effect of these agents is unknown.

Kidney failure

Patients with TIH and with signs of worsening of renal function should be appropriately evaluated, considering whether the potential benefits of treatment with Zometa outweigh any risks.

The decision to treat patients with bone metastases for the prevention of skeletal related events must take into account the fact that the treatment effect begins to manifest after 2-3 months.

Treatment with Zometa has been associated with reports of renal function disorders. Factors that may increase the risk of worsening of renal function include dehydration, pre-existing renal impairment, multiple courses of Zometa and other bisphosphonates as well as the use of other nephrotoxic drugs. Although the risk is reduced with administration of 4 mg zoledronic acid over 15 minutes, however, worsening of kidney function may occur. Worsening of renal function, progression to renal failure and dialysis have been reported in patients after the first dose or after a single 4 mg dose of zoledronic acid. An increase in serum creatinine may also be observed in some patients when Zometa is administered long-term and at the recommended dosage for the prevention of skeletal-related events, although such cases are less frequent.

The patient's serum creatinine levels should be assessed prior to administration of each dose of Zometa. It is recommended that zoledronium acid treatment be initiated at reduced doses in patients with bone metastases with mild to moderate renal impairment. In patients who show signs of renal impairment during treatment, treatment with Zometa should be discontinued. Zometa should only be reset when the serum creatinine value returns to within 10% of the baseline value. Treatment with Zometa should be resumed at the same strength as was used prior to stopping treatment.

In view of the potential impact of zoledronic acid on renal function, the lack of clinical safety data in patients with severe renal impairment (defined in clinical trials as serum creatinine ≥ 400 μmol / l or ≥ 4.5 mg / dl for patients with TIH and ≥ 265 μmol / L or ≥ 3.0 mg / dL for patients with cancer and bone metastases) at baseline and limited pharmacokinetic data in patients with severe renal impairment at baseline (creatinine clearance

Hepatic insufficiency

As clinical data available in patients with severe hepatic impairment are limited, it is not possible to make specific recommendations in this patient population.

Osteonecrosis of the mandible / maxilla

Osteonecrosis of the jaw has been reported as an uncommon event in clinical trials and in the post-marketing period in patients receiving Zometa.

The initiation of treatment or a new course of treatment should be postponed in patients with open non-healed soft tissue lesions of the oral cavity, except in medical emergency situations.Before initiating bisphosphonate treatment in patients with concomitant risk factors, a dental examination with appropriate preventive dental procedures and an individual benefit-risk assessment is recommended.

The following risk factors should be considered when assessing the individual risk of developing osteonecrosis of the jaw:

• potency of bisphosphonate (highest risk for products with greater potency), route of administration (highest risk for parenteral administration) and cumulative bisphosphonate dose.

• cancer, co-morbidities (eg anemia, coagulopathies, infection), smoking.

• concomitant therapies: chemotherapy, angiogenesis inhibitors (see section 4.5), radiotherapy to the neck and head, corticosteroids.

• history of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures (eg tooth extractions) and poorly fitting dentures.

All patients should be encouraged to maintain good oral hygiene, to undergo routine dental check-ups and to immediately report any oral symptoms such as tooth mobility, pain, swelling or non-healing of sores, or discharge during treatment with Zometa. In the course of treatment, invasive dental procedures should only be performed after careful consideration and avoided in close proximity to the administration of zoledronic acid. In patients who have developed osteonecrosis of the jaw during bisphosphonate therapy, dental surgery may 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 management program for patients who develop osteonecrosis of the jaw should be established in close collaboration between the treating physician and a dentist or oral surgeon competent in osteonecrosis of the jaw. Temporary interruption of zoledronic acid treatment should be considered until the condition resolves and concomitant risk factors are mitigated where possible.

Musculoskeletal pain

During post marketing experience severe and occasionally disabling bone, joint and / or muscle pain has been reported in patients treated with Zometa. However, these reports were infrequent. After initiation of treatment, time to onset of symptoms ranged from one day to several months. Most patients experienced "relief of symptoms after stopping" treatment. A subgroup experienced relapse of symptoms when receiving further treatment with Zometa or another bisphosphonate.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal 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 evidence of stress fractures, weeks or months before a hip fracture occurs. complete. 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.

Hypocalcemia

Cases of hypocalcaemia have been reported in patients treated with Zometa. Cardiac arrhythmias and neurological adverse events (including convulsions, hypoesthesia and tetany) secondary to cases of severe hypocalcaemia have been reported. Cases of severe hypocalcaemia requiring hospitalization have been reported. In some circumstances, hypocalcaemia can be life-threatening (see section 4.8). Particular caution is advised when Zometa is administered with medicinal products known to cause hypocalcaemia, as they may have a synergistic effect resulting in severe hypocalcaemia (see section 4.5) Serum calcium should be measured and hypocalcaemia treated before initiating therapy with Zometa. Patients should receive "adequate calcium and vitamin D supplementation.

04.5 Interactions with other medicinal products and other forms of interaction

In clinical studies, Zometa was administered concomitantly with commonly used anticancer drugs, diuretics, antibiotics and analgesics, with no clinically significant interactions observed. In vitro Zoledronic acid has been shown not to bind to plasma proteins and does not inhibit cytochrome P450 enzymes (see section 5.2) but no specific clinical interaction studies with other medicinal products have been performed.

Particular caution is advised when bisphosphonates are administered with aminoglycosides, calcitonin or loop diuretics, as these medicinal products may have an additive effect resulting in a decrease in calcium for longer periods than required (see section 4.4). .

Caution is advised when Zometa is administered with other potentially nephrotoxic medicinal products. Also pay attention to the possible occurrence of hypomagnesaemia during treatment.

In patients with multiple myeloma, the risk of kidney dysfunction may be increased when Zometa is used in combination with thalidomide.

Caution should be exercised when Zometa is administered with anti-angiogenic medicinal products as an increased incidence of ONJ cases has been observed in patients concomitantly treated with these medicinal products.

04.6 Pregnancy and breastfeeding

Pregnancy

There are no adequate data from the use of zoledronic acid in pregnant women. Reproduction studies with zoledronic acid in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Zometa it should not be used during pregnancy Women of childbearing potential should be advised to avoid becoming pregnant.

Pregnancy

It is not known whether zoledronic acid is excreted in human milk. Zometa is contraindicated in breastfeeding women (see section 4.3).

Fertility

Zoledronic acid was studied in rats for potential adverse effects on the fertility of the parents and the F1 generation. It showed very evident pharmacological effects considered related to the inhibition of the compound on skeletal calcium metabolism, resulting in hypocalcemia in the peripartum, an effect of bisphosphonate class, dystocia and early study closure. For this reason, these results precluded the definitive determination of the effects of zoledronic acid on human fertility.

04.7 Effects on ability to drive and use machines

Adverse reactions, such as dizziness and somnolence, may affect the ability to drive or use machines, therefore caution should be exercised in driving and using machines during treatment with Zometa.

04.8 Undesirable effects

Summary of the safety profile

Within three days of administration of Zometa, an acute phase reaction was commonly reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, stiffness and arthritis resulting in joint swelling; these symptoms generally resolved within a few days (see description of selected adverse events).

The following have been identified as important risks with the use of Zometa in the approved indications:

renal impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcemia, atrial fibrillation, anaphylaxis and interstitial lung disease. The frequencies for each of these identified risks are shown in Table 1.

Table of adverse reactions

The following adverse reactions, listed in Table 1, were derived from clinical studies and post-marketing reports following chronic administration of 4 mg zoledronic acid:

Table 1

Adverse reactions are ranked in order of frequency descending using the following convention: Very common (≥1 / 10), common (≥1 / 100,

Disorders of the blood and lymphatic system Common: Anemia Uncommon: Thrombocytopenia, leukopenia Rare: Pancytopenia Disorders of the immune system Uncommon: Hypersensitivity reactions Rare: Angioneurotic edema Psychiatric disorders Uncommon: Anxiety, sleep disturbance Rare: Confusion Nervous system disorders Common: Headache Uncommon: Vertigo, paraesthesia, dysgeusia, hypoesthesia, hyperesthesia, tremor, somnolence Very rare: Convulsions, hypoesthesia and tetany (secondary to hypocalcemia) Eye disorders Common: Conjunctivitis Uncommon: Blurred vision, scleritis and inflammation of the orbit Rare: Uveitis Very rare: Episcleritis Cardiac pathologies Uncommon: Hypertension, hypotension, atrial fibrillation, hypotension leading to syncope or circulatory collapse Rare: Bradycardia, cardiac arrhythmia (secondary to hypocalcaemia) Respiratory, thoracic and mediastinal disorders Uncommon: Dyspnea, cough, bronchoconstriction Rare Interstitial lung disease Gastrointestinal disorders Common: Nausea, vomiting, decreased appetite Uncommon: Diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth Skin and subcutaneous tissue disorders Uncommon: Pruritus, rash (including erythematous and macular rash), increased sweating Musculoskeletal and connective tissue disorders Common: Bone pain, myalgia, arthralgia, widespread pain Uncommon: Muscle spasms, osteonecrosis of the jaw / jaw Renal and urinary disorders Common: Renal impairment Uncommon: Acute renal failure, hematuria, proteinuria General disorders and administration site conditions Common: Fever, flu-like syndrome (including fatigue, chills, malaise and redness) Uncommon: Asthenia, peripheral edema, injection site reactions (including pain, irritation, swelling, induration), chest pain, weight gain, anaphylactic reaction / shock, urticaria Rare: Arthritis with joint swelling as a symptom of the acute phase reaction Diagnostic tests Very common: Hypophosphatemia Common: Increased creatinine and azotemia, hypocalcemia Uncommon: Hypomagnesemia, hypokalemia Rare: Hyperkalemia, hypernatremia

Description of selected adverse reactions

Impaired renal function

Zometa has been associated with reports of renal dysfunction. In an analysis of pooled safety data from pivotal studies of Zometa in the prevention of skeletal-related events in patients with advanced malignancies involving bone, the frequency of adverse events of renal impairment suspected to be related to the use of Zometa (adverse reactions) was as follows: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung cancer and other solid tumors (3 ,2%). Factors that may increase the possibility of worsening renal function include dehydration, pre-existing renal impairment, multiple courses of Zometa or other bisphosphonates, as well as concomitant use of nephrotoxic drugs or a shorter infusion time than is generally recommended. Renal impairment, progression to renal failure and dialysis have been reported in patients following the initial dose or a single 4 mg dose of zoledronic acid (see section 4.4).

Osteonecrosis of the mandible / maxilla

Cases of osteonecrosis of the jaw have been reported, mainly in cancer patients treated with medicinal products that inhibit bone resorption, such as Zometa (see section 4.4). Many of these patients were also receiving chemotherapy and corticosteroids and had evidence of localized infection, including osteomyelitis. The majority of the reports concern cancer patients undergoing tooth extractions or other dental surgeries.

Atrial fibrillation

In a 3-year, randomized, double-blind controlled study evaluating the efficacy and safety of zoledronic acid 5 mg once yearly versus placebo in the treatment of postmenopausal osteoporosis (OPM), the overall incidence of atrial fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving zoledronic acid 5 mg and placebo, respectively. The serious adverse event rate of atrial fibrillation was respectively at 1.3% (51 out of 3,862) and 0.6% (22 out of 3,852). The imbalance observed in this study was not observed in other studies with zoledronic acid, including those with Zometa (zoledronic acid) 4 mg every 3 -4 weeks in cancer patients. The mechanism underlying the increased incidence of atrial fibrillation in this single study is unknown.

Acute phase reaction

This adverse drug reaction includes a variety of symptoms including fever, myalgia, headache, pain in extremity, nausea, vomiting, diarrhea, arthralgia and arthritis resulting in joint swelling. The time to onset is ≤ 3 days after the Zometa infusion and the reaction is also referred to as "flu-like symptoms" or "post-dose" symptoms.

Atypical femur fractures

During post-marketing experience the following reactions have been reported (frequency rare):

Atypical subtrochanteric and diaphyseal fractures of the femur (bisphosphonate class adverse reaction).

Adverse reactions (ADRs) related to hypocalcemia

Hypocalcaemia is a major risk identified with Zometa in the approved indications. Based on the review of cases from both clinical trials and post-marketing use, there is sufficient evidence to support an association between Zometa therapy, reported events of hypocalcaemia and secondary development of cardiac arrhythmia. There is also evidence of an association between hypocalcaemia and secondary neurological events reported in these cases including seizures, hypoesthesia and tetany (see 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.

04.9 Overdose

Clinical experience with acute overdose of Zometa is limited. The erroneous administration of doses up to 48 mg of zoledronic acid has been reported. Patients who have been treated with higher than recommended doses (see section 4.2) should be monitored. with particular caution as renal impairment (including renal failure) and serum electrolyte abnormalities (including calcium, phosphorus and magnesium) have been observed. In case of hypocalcaemia, calcium gluconate infusions should be administered as clinically indicated.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Medicinal products for the treatment of bone diseases, bisphosphonates, ATC code: M05BA08.

Zoledronic acid belongs to the bisphosphonate class and acts mainly at the bone level. It is an inhibitor of osteoclastic bone absorption.

The selective action of bisphosphonates on bone tissue is due to their high affinity for mineralized bone but the exact molecular mechanism that determines the inhibition of osteoclastic activity is not yet known. Long-term studies in animals have shown that zoledronic acid inhibits bone resorption without adversely affecting bone formation, mineralization or mechanical properties.

In addition to being a potent inhibitor of bone resorption, zoledronic acid also possesses several anticancer properties that could contribute to its overall efficacy in the treatment of bone metastases. The following properties have been demonstrated in preclinical studies:

Live: inhibition of osteoclastic bone resorption which, by modifying the microenvironment of the bone marrow, makes it less suitable for the growth of tumor cells; antiangiogenic and pain-relieving activity.

In vitro: inhibition of osteoblast proliferation, direct cytostatic and proapoptotic activity on tumor cells, synergistic cytostatic effect with other anticancer drugs, adhesion and invasion inhibition activity.

Results of clinical trials in the prevention of skeletal related events in patients with advanced malignant tumors affecting the bone

In the first randomized, double-blind, placebo-controlled study, zoledronic acid 4 mg was compared with placebo for the prevention of skeletal-related events (SRE) in prostate cancer patients with bone metastases. Zoledronic acid 4 mg significantly reduced the percentage of patients with at least one skeletal related event (SRE), delayed median time to first SRE by> 5 months, and reduced annual event incidence per patient-report of skeletal morbidity. Multiple event analysis showed a 36% reduction in the risk of developing SRE in the 4 mg zoledronic acid group compared to placebo. Patients treated with 4 mg zoledronic acid reported less pain increase than patients treated with placebo, and the difference reached significance at months 3, 9, 21 and 24. Fewer patients treated with 4 mg zoledronic acid reported pathological fractures. The effects of treatment were less pronounced in patients with blastic lesions. The efficacy results are shown in Table 2.

In a second study, which included solid tumors other than breast cancer or prostate cancer, zoledronic acid 4 mg significantly reduced the percentage of patients with an SRE, significantly delayed the median time to first SRE by> 2 months and reduced the skeletal morbidity ratio. Multiple event analysis showed a 30.7% reduction in the risk of developing SRE in the 4 mg zoledronic acid group compared to placebo. The efficacy results are shown in Table 3. Table 2: Efficacy results (prostate cancer patients treated with hormone therapy)


Any SRE (+ TIH) Fractures * Radiotherapy to the bone zoledronic acid 4 mg Placebo zoledronic acid 4 mg Placebo zoledronic acid 4 mg Placebo No. 214 208 214 208 214 208 Percentage of patients with SRE (%) 38 49 17 25 26 33 Significance (p - value) 0,028 0,052 0,119 Median time to SRE (days) 488 321 NO NO NO 640 Significance (p - value) 0,009 0,020 0,055 Skeletal morbidity report 0,77 1,47 0,20 0,45 0,42 0,89 Significance (p - value) 0,005 0,023 0,060 Reduction of the risk of the onset of multiple events ** (%) 36 - NA NA NA NA Significance (p - value) 0,002 NA NA

* Includes vertebral and non-vertebral fractures

** Includes all skeletal events, total number as well as time to each event during the study

NR Not achieved

NA Not applicable

Table 3: Efficacy results (solid tumors other than breast or prostate cancer)


Any SRE (+ TIH) Fractures * Radiotherapy to the bone zoledronic acid 4 mg Placebo zoledronic acid 4 mg Placebo zoledronic acid 4 mg Placebo No. 257 250 257 250 257 250 Percentage of patients with SRE (%) 39 48 16 22 29 34 Significance (p - value) 0,039 0,064 0,173 Median time to SRE (days) 236 155 NO NO 424 307 Significance (p - value) 0,009 0,020 0,079 Skeletal morbidity report 1,74 2,71 0,39 0,63 1,24 1,89 Significance (p - value) 0,012 0,066 0,099 Reduction of the risk of the onset of multiple events ** (%) 30,7 - NA NA NA NA Significance (p - value) 0,003 NA NA

* Includes vertebral and non-vertebral fractures

** Includes all skeletal events, total number as well as time to each event during the study

NR Not achieved

NA Not applicable

In a third, randomized, double-blind phase III study, zoledronic acid 4 mg and pamidronate 90 mg administered every 3 to 4 weeks were compared in patients with multiple myeloma or breast cancer with at least one bone lesion. The results demonstrated that treatment with 4 mg zoledronic acid produced comparable efficacy to that obtained with pamidronate 90 mg for the prevention of SREs. Multiple event analysis showed a significant 16% reduction in the risk of developing SRE in patients treated with 4 mg zoledronic acid compared to those treated with pamidronate. Efficacy results are shown in Table 4.

Table 4: Efficacy Results (Breast Cancer and Multiple Myeloma Patients)


Any SRE (+ TIH) Fractures * Radiotherapy to the bone zoledronic acid 4 mg Pam 90 mg zoledronic acid 4 mg Pam 90 mg zoledronic acid 4 mg Pam 90 mg No. 561 555 561 555 561 555 Percentage of patients with SRE (%) 48 52 37 39 19 24 Significance (p - value) 0,198 0,653 0,037 Median time to SRE (days) 376 356 NO 714 NO NO Significance (p - value) 0,151 0,672 0,026 Skeletal morbidity report 1,04 1,39 0,53 0,60 0,47 0,71 Significance (p - value) 0,084 0,614 0,015 Reduction of the risk of the onset of multiple events ** (%) 16 - NA NA NA NA Significance (p - value) 0,030 NA NA

* Includes vertebral and non-vertebral fractures

** Includes all skeletal events, total number as well as time to each event during the study

NR Not achieved

NA Not applicable

Zoledronic acid 4 mg was also studied in 228 patients with documented bone metastases from breast cancer in a double-blind, randomized, placebo-controlled study to evaluate the effect of 4 mg zoledronic acid on the skeletal morbidity ratio (SRE ), calculated as the total number of skeletal related events (SRE) (excluding hypercalcemia and corrected for previous fracture), divided by the total risk time. The patients took 4 mg of zoledronic acid or placebo every four weeks for one year. Patients were evenly distributed between the zoledronic acid and placebo treatment groups.

The SRE (events / person year) ratio was 0.628 for zoledronic acid and 1.096 for placebo. The proportion of patients with at least one SRE (excluding hypercalcaemia) was 29.8% in the zoledronic acid treatment group compared with 49.6% in the placebo group (p = 0.003). In the zoledronic acid treatment group, the median time to onset of the first SRE was not reached over the study duration and was significantly prolonged compared to placebo (p = 0.007) Multiple event analysis (risk ratio = 0.59, p = 0.019) showed a 41% reduction in the risk of developing SRE in the 4 mg zoledronic acid group compared to placebo.

A statistically significant improvement in pain score (assessed by the Brief Pain Inventory, BPI) was observed in the zoledronic acid treatment group starting at week 4 and for all subsequent evaluations made during the study compared to placebo. For zoledronic acid the pain score was consistently below baseline and pain reduction was associated with a trend in the decrease in pain therapy score.

Results of clinical trials in the treatment of TIH

Clinical studies in neoplastic hypercalcaemia (TIH) have shown that the effect of zoledronic acid is characterized by a decrease in calcium and urinary calcium excretion. In phase I dose finding studies in patients with mild to moderate neoplastic hypercalcaemia (TIH) the effective doses tested were approximately in the range of 1.2-2.5 mg.

To verify the effects of 4 mg zoledronic acid in comparison to pamidronate at a dose of 90 mg, the results of two "pivotal" multicenter clinical trials in patients with TIH were pooled for a "pre-defined analysis. The acid" zoledronic at 8 mg, demonstrated faster normalization of serum calcium concentration on day 4 and, at 4 mg and 8 mg, on day 7. The following response rates were observed:

Table 5: Percentage of patients who showed a complete response, (per day) in the pooled studies in TIH


Day 4 Day 7 Day 10 Zoledronic acid 4 mg (N = 86) 45.3% (p = 0.104) 82.6% (p = 0.005) * 88.4% (p = 0.002) * Zoledronic acid 8 mg (N = 90) 55.6% (p = 0.021) * 83.3% (p = 0.010) * 86.7% (p = 0.015) * Pamidronate 90 mg (N = 99) 33,3% 63,6% 69,7% * p-values ​​compared to pamidronate.

The median time to normalization of calcium was 4 days. Median time to relapse (new increase in serum albumin corrected calcium ≥ 2.9 mmol / L) ranged from 30 to 40 days in patients treated with zoledronic acid compared to 17 days in patients treated with pamidronate 90 mg (p : 0.001 for the 4 mg dose and 0.007 for the 8 mg dose). There are no statistically significant differences between the two different doses of zoledronic acid.

In clinical trials, 69 patients who relapsed or were refractory to initial treatment (doses of 4 mg, 8 mg zoledronic acid or 90 mg pamidronate) were further treated with 8 mg zoledronic acid. The response to treatment in these patients was approximately 52%. As these patients were further treated with the 8 mg dose only, no data is available to allow comparison with the 4 mg dose.

In clinical studies in patients with neoplastic hypercalcaemia (TIH), the overall safety profile between all three treatment groups (zoledronic acid 4 mg and 8 mg and pamidronate 90 mg) was similar in type and severity.

Pediatric population

Results of clinical studies in the treatment of severe osteogenesis imperfecta, in pediatric patients from 1 to 17 years of age

The effects of intravenous infusion of zoledronic acid in the treatment of pediatric patients (aged 1 to 17 years) with severe osteogenesis imperfecta (types I, III and IV) were compared with intravenous infusion of pamidronate in an international study. , multicentre, randomized, open label with 74 and 76 patients in each treatment group, respectively. The study treatment period was 12 months, preceded by a 4-9 week screening period during which vitamin D and calcium supplements were given for at least 2 weeks. In the clinical program, patients aged 1 to 3 years received 0.025 mg / kg zoledronic acid (up to a maximum single dose of 0.35 mg) every 3 months and patients aged 3 to 17 years received 0 0.05 mg / kg zoledronic acid (up to a maximum single dose of 0.83 mg) every 3 months. An extension study was conducted to evaluate the long-term general and renal safety profile of zoledronic acid administered once or twice a year, for an additional 12 months, in children who had completed one year. treatment with zoledronic acid or pamidronate in the main study.

The primary endpoint of the study was the percent change from baseline in lumbar spine bone mineral density (BMD) after 12 months of treatment. The expected effects of treatment on BMD were similar, but the study design was not robust enough to establish the non-inferior efficacy of zoledronic acid. In particular, there was no clear evidence of efficacy on fracture incidence or pain. Adverse events with long bone fractures of the lower extremities were reported in approximately 24% (femur) and 14% (tibia) of patients with severe osteogenesis imperfecta treated with zoledronic acid, versus 12% and 5% of treated patients. with pamidronate, regardless of disease type and causal relationship, but the overall incidence of fractures was comparable between patients treated with zoledronic acid and pamidronate: 43% (32/74) vs 41% (31/76). Interpretation of fracture risk is made difficult by the fact that fractures are common events in patients with severe osteogenesis imperfecta as part of the disease process.

The type of adverse reactions observed in this population was similar to that previously observed in adults with advanced malignancies involving bone (see section 4.8). Adverse reactions, ranked in order of frequency, are presented in Table 6. Adverse reactions are classified according to the following convention: very common (≥1 / 10), common (≥1 / 100,

Table 6: Adverse reactions observed in pediatric patients with severe osteogenesis imperfecta 1


Nervous system disorders Common: Headache Cardiac pathologies Common: Tachycardia Respiratory, thoracic and mediastinal disorders Common: Nasopharyngitis Gastrointestinal disorders Very common: Vomiting, nausea Common: Abdominal pain Musculoskeletal and connective tissue disorders Common: Pain in extremities, arthralgia, musculoskeletal pain General disorders and administration site conditions Very common: Pyrexia, fatigue Common: Acute phase reaction, pain Diagnostic tests Very common: Hypocalcemia Common: Hypophosphatemia

1 Adverse events that occurred with a frequency

In pediatric patients with severe osteogenesis imperfecta, zoledronic acid, compared to pamidronate, appears to be associated with more pronounced risks of acute phase reaction, hypocalcaemia and unexplained tachycardia, but this difference is reduced after subsequent infusions.

The European Medicines Agency has waived the obligation to submit the results of studies with zoledronic acid in all subsets of the pediatric population for the treatment of neoplastic hypercalcaemia and the prevention of skeletal-related events in affected patients. from advanced malignant tumors involving bone (see section 4.2 for information on pediatric use).

05.2 Pharmacokinetic properties

Pharmacokinetic studies following single and repeated 5 and 15 minute intravenous infusions of 2, 4, 8 and 16 mg of zoledronic acid in 64 patients with bone metastases have shown the following results regardless of dosage.

After initiating the zoledronic acid infusion, plasma concentrations of zoledronic acid rise rapidly, peaking at the end of the infusion period, followed by a rapid decline to a concentration

Zoledronic acid, administered intravenously, is eliminated according to a process that takes place in three phases: rapid disappearance of the drug from the systemic circulation, with a biphasic course, with a plasma half-life of (t½α) 0.24 and (t½β) 1, 87 hours, followed by a slow elimination phase with terminal elimination half-life of (t½γ) 146 hours. There is no accumulation of zoledronic acid in plasma after multiple doses administered every 28 days. Zoledronic acid is not metabolised and is excreted unchanged via the kidneys. After the first 24 hours, 39 ± 16% of the administered dose is present in the urine, while the remainder is mainly bound to bone tissue. Much is released from bone tissue. slowly into the systemic circulation and then eliminated via the kidney. Body clearance is 5.04 ± 2.5 l / h, regardless of dose and is not influenced by gender, age, race and body weight. The increase in infusion time 5 to 15 minutes produced a 30% decrease in zoledronic acid concentration at the end of the infusion but did not change the area under the curve (plasma concentration versus time).

As with other bisphosphonates, the inter-patient variability in pharmacokinetic parameters for zoledronic acid was high.

No pharmacokinetic data are available for zoledronic acid in patients with hypercalcaemia or in patients with hepatic insufficiency. In vitro, zoledronic acid does not inhibit human cytochrome P450 enzymes, does not exhibit biotransformation and a quantity of faeces in animal studies, supporting the fact that there is no relevant role for hepatic function in the pharmacokinetics of zoledronic acid.

Renal clearance of zoledronic acid was correlated with creatinine clearance, accounting for renal clearance 75 ± 33% of creatinine clearance, which averaged 84 ± 29 ml / min (range 22 to 143 ml / min) in the 64 cancer patients studied. Population analyzes showed that for a patient with a creatinine clearance of 20 ml / min (severe renal impairment), or 50 ml / min (moderate renal impairment), the corresponding clearance predicted for the zoledronic acid should correspond to 37% or 72% respectively of that of a patient with a creatinine clearance of 84 ml / min. Only limited pharmacokinetic data are available in patients with severe renal impairment (creatinine clearance

In an in vitro study, zoledronic acid showed a low affinity for cellular components of human blood, with a mean plasma concentration rate of 0.59% over a range of 30 ng / mL to 5000 ng / mL. Plasma protein binding is low, with the free fraction ranging from 60% at 2 ng / mL to 77% at 2000 ng / mL of zoledronic acid.

Particular categories of patients

Pediatric patients

Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that the pharmacokinetics of zoledronic acid in children 3 to 17 years of age are similar to that in adults when considering a similar dose level (mg / kg). , body weight, gender and creatinine clearance do not appear to influence the systemic exposure of zoledronic acid.

05.3 Preclinical safety data

Acute toxicity

The maximum non-lethal dose for single intravenous administration was 10 mg / kg body weight in the mouse and 0.6 mg / kg in the rat.

Subchronic and chronic toxicity

The tolerability of zoledronic acid was good after subcutaneous administration in the rat and intravenous administration in the dog at doses up to 0.02 mg / kg / day for 4 weeks. Subcutaneous administration of 0.001 mg / kg / day in the rat and intravenous administration of 0.005 mg / kg every 2-3 days in dogs up to 52 weeks was well tolerated.

The most frequent finding in repeat dose studies is an increase in spongy bone tissue in the metaphyses of long bones in developing animals at approximately all doses, reflecting the pharmacological activity of the product on bone resorption.

Safety margins for renal effects have been shown to be small in long-term studies in animals at repeated parenteral doses but the cumulative no adverse event levels (NOAELs) per single dose (1.6 mg / kg) and multiple dose studies up to one month (0.06-0.6 mg / kg / day) have shown no renal consequences at doses equivalent to or exceeding the maximum therapeutic dose in humans. Long-term repeated administration of dose groups within the maximum therapeutic dose used in humans for zoledronic acid produced toxic effects in other organs including the gastrointestinal tract, liver, spleen and lungs, as well as at injection sites.

Reproductive function toxicity studies

Zoledronic acid was shown to be teratogenic in the rat after subcutaneous administration of doses ≥ 0.2 mg / kg. Maternal toxicity was observed in the rabbit although no teratogenic or foetotoxic effects were observed. At the lowest dose tested in the rat (0 , 01 mg / kg body weight) dystocia was observed.

Mutagenesis and carcinogenesis

In the mutagenicity tests conducted, zoledronic acid was shown to have no mutagenic effects or carcinogenic potential.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Powder vial: Mannitol

Sodium citrate

Solvent ampoule: Water for injections

06.2 Incompatibility

To avoid potential incompatibilities, the reconstituted Zometa solution must be diluted with 0.9% w / v saline or 5% w / v glucose solution.

This medicinal product must not be mixed with solutions for infusion containing calcium or other divalent cations such as lactated Ringer's solution, and must be administered as a single intravenous solution in a separate infusion line.

06.3 Period of validity

3 years.

After reconstitution and dilution: From a microbiological point of view, the reconstituted and diluted solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 C - 8 C. The refrigerated solution should be brought to temperature. environment prior to administration.

06.4 Special precautions for storage

This medicine does not require any special storage conditions.

For storage conditions of the reconstituted solution for infusion, see section 6.3.

06.5 Nature of the immediate packaging and contents of the package

Powder vial: 6 ml colorless glass vials, type I hydrolytic grade glass (Ph. Eur.).

Solvent vial: 5ml colorless glass vial.

Single packs containing respectively 1 or 4 vials and 1 or 4 ampoules of water for injections.

Multipacks containing 10 (10 packs of 1 + 1) vials and ampoules of water for injections.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling

The powder must be previously reconstituted in 5 ml of water for injections using the special vial included in the product package. The dissolution of the powder must be complete before taking the solution for further dilution. The required amount of reconstituted solution should be further diluted in 100 ml of calcium-free solution for infusion (0.9% w / v saline or 5% w / v glucose solution).

Additional information on handling of Zometa, including guidance on preparing reduced doses, is provided in section 4.2.

Aseptic techniques must be followed during preparation of the infusion. For single use only.

Only the clear solution, free from visible particles and colorless, should be used.

Healthcare professionals should be advised not to dispose of unused Zometa through the household waste system.

Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.

07.0 MARKETING AUTHORIZATION HOLDER

Novartis Europharm Limited

Frimley Business Park

Camberley GU16 7SR

UK

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/01/176 / 001-003

035263033

035263019

035263021

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 20.03.2001

Date of most recent renewal: 20.03.2006

10.0 DATE OF REVISION OF THE TEXT

D.CCE July 2015

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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