APPROVED BY

Order of Ministry of Healthcare of Ukraine

19.08.2015 № 527

Registration certificate

№ UA/14498/01/01

 

 

INSTRUCTION

for medical use of the preparation

ZOLEUM

 

Composition:

Active substance: zoledronic acid;

5 mg of concentrate contains zoledronic acid monohydrate equivalent to zoledronic acid  4 mg;

Excipients: Sodium citrate (E 331), mannitol (E421), water for injections.

Pharmaceutical form. Concentrate for infusion solution.

Basic physical and chemical properties: clear and colorless solution without visible particles.

Pharmacotherapeutic group. Drugs for treatment of bone diseases. Bisphosphonates.

ATC code: М05ВА08.

Pharmacodynamic properties.

Pharmacotherapeutic properties.

Zoledronic acid belongs to the class of bisphosphonates and acts primarily on bone. It is one of powerful inhibitors of osteoclastic bone resorption.

The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting the formation, mineralisation or mechanical properties of bone.

In addition to being a potent inhibitor of bone resorption, zoledronic acid has a direct anti-tumor effect on cultured myeloma cells and human breast cancer through the inhibition of cell proliferation and apoptosis induction. This indicates that zoledronic acid may have antimetastatic properties.

- In vivo: Inhibition of osteoclastic bone resorption, which alters the bone marrow microenvironment, making it less conducive to tumour cell growth, anti-angiogenic activity and anti-pain activity.

- In vitro: Inhibition of osteoblast proliferation, direct cytostatic and pro-apoptotic activity on tumour cells, synergistic cytostatic effect with other anti-cancer drugs, anti- adhesion/invasion activity.

Pharmacokinetic properties

Single and multiple 5 and 15-minute infusions of 2, 4, 8 and 16 mg zoledronic acid in 64 patients yielded the following pharmacokinetic data, which were found to be dose independent.

After initiating the infusion of zoledronic acid, the plasma concentrations of zoledronic acid rapidly increased, achieving their peak at the end of the infusion period, followed by a rapid decline to < 10% of peak after 4 hours and < 1% of peak after 24 hours, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak prior to the second infusion of zoledronic acid on day 28. Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of t_½α 0.24 and t_½β 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t_½γ 146 hours. There was no accumulation of zoledronic acid in plasma after multiple doses given every 28 days. Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. From the bone tissue it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04 ± 2.5 l/h, independent of dose, and unaffected by gender, age, race, and body weight. Increasing the infusion time from 5 to 15 minutes caused a 30% decrease in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.

The interpatient variability in pharmacokinetic parameters for zoledronic acid was high, as seen with other bisphosphonates.

No pharmacokinetic data for zoledronic acid are available in patients with hypercalcaemia or in patients with hepatic insufficiency. Zoledronic acid does not inhibit human P450 enzymes in vitro, shows no biotransformation and in animal studies < 3% of the administered dose was recovered in the faeces, suggesting no relevant role of liver function in the pharmacokinetics of zoledronic acid.

The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 5 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 ml/min (range 22 to 143 ml/min) in the 64 cancer patients studied. Population analysis showed that for a patient with creatinine clearance of 20 ml/min (severe renal impairment), or 50 ml/min (moderate impairment), the corresponding predicted clearance of zoledronic acid would be 37% or 72%, respectively.

The low affinity of zoledronic acid with cellular components of blood has revealed. Binding to plasma proteins is low (about 56%) and independent of acid concentration.

Special populations

Paediatric patients

Limited pharmacokinetic data in children with severe osteogenesis imperfecta suggest that zoledronic acid pharmacokinetics in children aged 3 to 17 years are similar to those in adults at a similar mg/kg dose level. Age, body weight, gender and creatinine clearance appear to have no effect on zoledronic acid systemic exposure.

Clinical particulars.

Therapeutic indications.

– Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies.

– Treatment of adult patients with tumour-induced hypercalcaemia.

Contraindications.

Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients involved in composition of medical preparation.

Interaction with other medicinal products and other forms of interaction.

In clinical studies, zoledronic acid has been administered concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring. 

Zoledronic acid shows no appreciable binding to plasma proteins and does not inhibit human P450 enzymes in vitro, but no formal clinical interaction studies have been performed.

Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required. Caution is advised when bisphosphonates are administered with loop diuretics, since these agents may have an additive effect, resulting in the possibility of hypocalcemia. Caution is indicated when Zoleum is used with other potentially nephrotoxic medicinal products. Attention should also be paid to the possibility of hypomagnesaemia developing during treatment.

There are no clinically significant interactions in intravenous introduction of bisphosphonates in combination with thalidomide in multiple myeloma patients.

There were reports of osteonecrosis of the jaw in patients treated concomitantly with zoledronic acid and anti-angiogenic (reduced blood supply to the tumor) medicinal products.

Precautions for use.

General

All Patients including those with mild and moderate renal dysfunction must be assessed prior to administration of Zoleum to ensure that they are adequately hydrated.

Overhydration should be avoided in patients at risk of cardiac failure.

Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate and magnesium, should be carefully monitored after initiating Zoleum therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term supplemental therapy may be necessary. Untreated hypercalcaemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered.

Patients being treated with Zoleum should not be treated concomitantly with any other medicines containing zoledronic acid.

Patients being treated with Zoleum should not be treated concomitantly with any other bisphosphonates.

Renal insufficiency

Patients with TIH and evidence of deterioration in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of treatment with Zoleum acid outweighs the possible risk.

The decision to treat patients with bone metastases for the prevention of spine related diseases should consider that the onset of treatment effect is 2–3 months.

Bisphosphonates have been associated with reports of renal dysfunction. Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of Zoleum and other bisphosphonates as well as use of other nephrotoxic medicinal products or infusion in a short-term period than was recommended. While the risk is reduced with a dose of 4 mg Zoleum administered over 15 minutes, deterioration in renal function may still occur.

Increases in serum creatinine also occur in some patients with chronic administration of zoledronic acid at recommended doses for prevention of skeletal related events, although less frequently.

Patients should have their serum creatinine levels assessed prior to each dose of Zoleum. Upon initiation of treatment in patients with bone metastases and in women with early stage of breast cancer in postmenopausal period during treatment with aromatase inhibitors (AIs) to prevent the loss of bone mass and bone fractures with mild or moderate renal impairment, lower doses of Zoleum are recommended. (see Table in section «Way of Administration and Dosage»). In patients who show evidence of renal deterioration during treatment, Zoleum should only be resumed when serum creatinine returns to within 10% of baseline.

In view of the potential impact of Zoleum on renal function, the lack of clinical safety data in patients with severe renal impairment (in clinical trials defined 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 bone metastases and in women with early stage of breast cancer in postmenopausal period during treatment with aromatase inhibitors (AIs) to prevent the loss of bone mass and bone fractures, respectively) and only limited pharmacokinetic data in patients with severe renal impairment at baseline (creatinine clearance < 30 ml/min), the use of Zoleum is not recommended in patients with severe renal impairment..

Hepatic insufficiency

As only limited clinical data are available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.

Osteonecrosis of the jaw

Osteonecrosis of the jaw was reported predominantly in cancer patients with prescribed treatment regimens which include bisphosphonates, including zoledronic acid. Many of these patients were also prescribed chemotherapy and corticosteroids. Most of the recorded cases have been associated with dental procedures such as tooth extraction. Many of the patients had signs of local infection, including osteomyelitis.

Before starting the bisphosphonates treatment, an oral examination with appropriate dental prevention should be carried out for patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroid therapy, inadequate oral hygiene).

During the treatment these patients should avoid invasive dental procedures. Dental surgery may impair the condition of patients with bisphosphonate therapy who developed osteonecrosis of the jaw. There are no data, regarding patients requiring dental procedures, to determine whether the discontinuation of bisphosphonates reduces the risk of osteonecrosis of the jaw or not. When a doctor gives clinical assessment, he should consider the management plan of each patient based on individual benefit-risk analysis.

Musculoskeletal pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates. However, such reports have been infrequent. This group of drugs includes Zoleum (zoledronic acid). The time to onset of symptoms varied from one day to several months after starting treatment. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with zoledronic acid or another bisphosphonate.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Pregnancy and lactation.

The preparation is contraindicated during pregnancy and breast-feeding period.

Effects on ability to drive and use machines.

Studies to determine the effect of preparation on the ability to drive and use machines have not been conducted. However, based on adverse reactions you shouldn’t drive vehicles and use operating machines during the use of preparation.

Way of administration and dosage.

Zoleum must only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates.

Before the introduction of concentrate 4 mg Zoleum is diluted in 100 ml of 0.9% sodium chloride or 5% glucose solution. Prepared Zoleum solution for infusion is administered as a single intravenous infusion during at least 15 minutes.

Zoleum concentrate should not be mixed with infusion solutions containing calcium or other divalent cations such as Ringer's lactate solution. It should be administered as a single intravenous infusion using a single infusion system.

Prevention of skeletal related events in patients with advanced malignancies involving bone

Adults and older people

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

Patients should also be administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily.

Treatment of TIH

Adults and older people

The recommended dose in hypercalcaemia is a single dose of 4 mg zoledronic acid. Before and during administration of Zoleum it is necessary to ensure adequate hydration of the patient

Renal impairment

TIH

Zoleum treatment in TIH patients who also have severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, 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 < 400 µmol/l or < 4.5 mg/dl.

Prevention of skeletal related events in patients with advanced malignancies involving bone:

When initiating treatment with Zoleum in patients with multiple myeloma or metastatic bone lesions from solid tumours, serum creatinine and creatinine clearance (CLcr) should be determined. CLcr is calculated from serum creatinine using the Cockcroft-Gault formula. Zoleum is not recommended for patients presenting with severe renal impairment prior to initiation of therapy, which is defined for this population as CLcr < 30 ml/min. In clinical trials with zoledronic acid, patients with serum creatinine > 265 µmol/l or > 3.0 mg/dl were excluded.

In patients with bone metastases presenting with mild to moderate renal impairment prior to initiation of therapy (creatinine clearance 30-60 ml / min), the following doses are recommended:

Baseline creatinine clearance (ml/min)	recommended dose* (mg)
>60	4
50-60	3,5*
40-49	3,3*
30-39	3*

*Doses have been calculated assuming target AUC of 0.66 (mg•hr/l) (CLcr = 75 ml/min). The reduced doses for patients with renal impairment are expected to achieve the same AUC as that seen in patients with creatinine clearance of 75 ml/min.

 

Following initiation of therapy, serum creatinine should be measured prior to each dose of Zerlinda and treatment should be withheld if renal function has deteriorated. In the clinical trials, renal deterioration was defined as follows:

– For patients with normal baseline serum creatinine (< 1.4 mg/dl or < 124 µmol/l), an increase of 0.5 mg/dl or 44 µmol/l;

– For patients with abnormal baseline creatinine (> 1.4 mg/dl or > 124 µmol/l), an increase of 1.0 mg/dl or 88 µmol/l.

In the clinical studies, zoledronic acid treatment was resumed only when the creatinine level returned to within 10% of the baseline value. Zoleum treatment should be resumed at the same dose as that given prior to treatment interruption.

Instructions for preparation of Zoleum doses

The doses of concentrate for solution for infusion in milliliters (ml) that meet the doses of Zoleum in milligrams (mg):

– 4,4 ml equivalent to  3,5 mg;

– 4,1 ml equivalent to  3,3 mg;

– 3,8 ml equivalent to  3 mg.

The required amount of liquid concentrate should be diluted in 100 ml of sterile 0.9% sodium chloride or 5% glucose for intravenous infusion.

Children.

Safety and efficacy of zoledronic acid for children was not determined.

Overdose.

Clinical experience with acute overdose of zoledronic acid is limited. Patients who have received doses higher than those recommended should be carefully monitored, since renal function impairment (including renal failure) and serum electrolyte (including calcium, phosphorus and magnesium) abnormalities have been observed. In the event of hypocalcaemia, calcium gluconate infusions should be administered as clinically indicated. Treatment is symptomatic.

Adverse reactions.

Within three days after zoledronic acid administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis with subsequent joint swelling. These symptoms usually resolve within a few days.

The following are the important identified risks with Zoleum in the approved indications:

Renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, atrial fibrillation, anaphylaxis

The information about frequency of adverse reactions, during the use of Zoleum in the dose 4 mg, is based on data, received when long-term treatment was conducted. Adverse reactions associated with the use of Zoleum are similar to those that have been reported with other bisphosphonates and can be developed approximately in one third of all patients.

The mentioned below information about adverse reactions was collected during clinical trials after long-term treatment with zoledronic acid.

Adverse reactions are classified by the frequency of occurrence: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), including isolated reports.

Blood and lymphatic system disorders: Common – Anaemia; Uncommon – Thrombocytopenia, leukopenia; Rare – Pancytopenia.

Nervous system disorders: Common – Headache; Uncommon – Dizziness, paraesthesia, dysgeusia, hypoaesthesia, hyperaesthesia, tremor, somnolence.

Psychiatric disorders: Common – Sleep disturbance; Uncommon – Anxiety; Rare – Confusion.

Eye disorders: Common – Conjunctivitis; Uncommon – Blurred vision, scleritis and orbital inflammation; Very rare – Uveitis, Episcleritis.

Gastrointestinal disorders: Common – Nausea, vomiting, anorexia; Uncommon – Diarrhoea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.

Respiratory, thoracic and mediastinal disorders: Uncommon – Dyspnoea, cough, bronchoconstriction.

Skin and subcutaneous tissue disorders: Common – Hyperhidrosis; Uncommon – Pruritus, rash (including erythematous and macular rash), increased sweating.

Musculoskeletal and connective tissue disorders: Common – Bone pain, myalgia, arthralgia, generalised pain; Uncommon – Muscle spasms, osteonecrosis of the jaw *.

Cardiovascular disorders: Uncommon – Hypertension, hypotension, atrial fibrillation, hypotension leading to syncope or circulatory collapse; Rare – Bradycardia.

Renal and urinary disorders: Common – Renal impairment; Uncommon – Acute renal failure, haematuria, proteinuria.

Immune system disorders: Uncommon – Hypersensitivity reaction; Rare – Angioneurotic oedema.

General disorders and administration site conditions: Common – Fever, flu-like syndrome (including fatigue, rigors, malaise and flushing); Uncommon – Asthenia, peripheral oedema, injection site reactions (including pain, irritation, swelling, induration), chest pain, weight increase, anaphylactic reaction/shock, urticaria.

Investigations: Very common – Hypophosphataemia; Common – Blood creatinine and blood urea increased, hypocalcaemia; Uncommon – Hypomagnesaemia, hypokalaemia; Rare – Hyperkalaemia, hypernatraemia.

* Based on clinical trials with the examination of cases of osteonecrosis of the jaw.

Renal function impairment

There were reports of renal dysfunction in the use of zoledronic acid. Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of zoledronic acid or other bisphosphonates, as well as concomitant use of nephrotoxic medicinal products or using a shorter infusion time than currently recommended. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of 4 mg zoledronic acid.

Osteonecrosis of the jaw

Cases of osteonecrosis (mainly jaw) have been reported, predominantly in cancer patients treated with zoledronic acid. Many of these patients had signs of local infection including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has many risk factors, including diagnosed cancer, concomitant therapy (e.g. chemotherapy, radiotherapy, corticosteroids) and concomitant diseases (such as anemia, coagulopathy, infection and mouth disease).

As a cause-effect relation has not been proved, so we recommend patients to avoid invasive dental procedures.

Atrial fibrillation

In randomised, double-blind controlled trial that evaluated the efficacy and safety of zoledronic acid in patients with postmenopausal osteoporosis, the overall incidence of atrial fibrillation was 2.5% and 1,9% in patients treated withzoledronic acid 5 mg and placebo, respectively. The cause of the increased incidence of atrial fibrillation is unknown.

Acute phase reaction

These adverse reactions include fever, myalgia, headache, extremity pain, nausea, vomiting, diarrhea and arthralgia which might occur in first 3 days after Zoleum infusion.

Atypical fractures of the femur

During post-marketing experience the following reactions have been reported (frequency rare): Atypical subtrochanteric and diaphyseal femoral fractures (bisphopsphonate class adverse reaction).

Shelf life. 2 years.

Special precautions for storage.  

The prepared solution is stable for 24 hours at 2-8 ° C.

Before use, the frozen solution must be heated to room temperature.

Incompatibility.

Zoleum concentrate should be diluted in sterile 0.9% sodium chloride or 5% glucose solution. Zoleum concentrate should not be mixed with infusion solutions containing calcium or other divalent cations such as Ringer's lactate solution. It should be administered as a one-time infusion using a separate system for infusion.

Trials on glass bottles, as well as several types of infusion bags and infusion systems made of PVC, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride or 5% glucose solution), showed no incompatibility with the aforementioned packing materials.

Packaging.

5 ml of concentrate for solution for infusion in a glass vial closed with rubber stopper and aluminium cap with flip-off, which provides the first opening control.

1 vial in a carton box

Terms of dispensing. On prescription.

Manufacturer.

Laboratorio Italiano Biochimico Farmaceutico Lisapharma S.P.A.

Manufacturer’s registered address.

Via Licinio, 11, 22036 Erba (CO), Italy.

Applicant.

Ananta Medicare Ltd.

Applicant’s registered address.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Date of last update.

19.08.2015