Zoledronic Acid 5 Mg / 100 Ml Solution For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zoledronic acid 5 mg/100 ml solution for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial with 100 ml of solution contains 5 mg zoledronic acid (as monohydrate).
Each ml of the solution contains zoledronic acid monohydrate corresponding to 0.05 mg zoledronic acid
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for infusion
Clear and colourless solution pH: 6.0-7.0
Osmolality: 270-310 mOsmol/Kg
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of osteoporosis
- in post-menopausal women
- in adult men
at increased risk of fracture, including those with a recent low-trauma hip fracture.
Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy
- in post-menopausal women
- in adult men
at increased risk of fracture.
4.2 Posology and method of administration
Posology
Patients must be appropriately hydrated prior to administration of zoledronic acid. This is especially important for the elderly (> 65 years) and for patients receiving diuretic therapy.
Adequate calcium and vitamin D intake are recommended in association with zoledronic acid administration.
Osteoporosis
For the treatment of post-menopausal osteoporosis, osteoporosis in men and the treatment of osteoporosis associated with long-term systemic glucocorticoid therapy, the recommended dose is a single intravenous infusion of 5 mg zoledronic acid administered once a year.
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of zoledronic acid on an individual patient basis, particularly after 5 or more years of use.
In patients with a recent low-trauma hip fracture, it is recommended to give the zoledronic acid infusion at least two weeks after hip fracture repair (see section 5.1). In patients with a recent low-trauma hip fracture, a loading dose of 50 000 to 125 000 IU of vitamin D given orally or via the intramuscular route is recommended prior to the first zoledronic acid infusion.
Paget’s disease
For the treatment of Paget’s disease, zoledronic acid should be prescribed only by physicians with experience in the treatment of Paget’s disease of the bone. The recommended dose is a single intravenous infusion of 5 mg zoledronic acid. In patients with Paget’s disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following zoledronic acid administration (see section 4.4).
Re-treatment of Paget’s disease: after initial treatment with zoledronic acid in Paget’s disease, an extended remission period is observed in responding patients. Retreatment consists of an additional intravenous infusion of 5 mg zoledronic acid after an interval of one year or longer from initial treatment in patients who have relapsed. Limited data on re-treatment of Paget’s disease are available (see section 5.1).
Special _ populations Patients with renal impairment
Zoledronic acid is contraindicated in patients with creatinine clearance < 35 ml/min (see sections 4.3 and 4.4).
No dose adjustment is necessary in patients with creatinine clearance > 35 ml/min. Patients with hepatic impairment
No dose adjustment is required (see section 5.2).
Elderly (>65years)
No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger subjects.
Paediatric population
The safety and efficacy of zoledronic acid in children and adolescents below 18 years of age have not been established. No data are available.
Method of administration Intravenous use.
Zoledronic acid (5 mg in 100 ml ready-to-infuse solution) is administered via a vented infusion line and given slowly at a constant infusion rate. The infusion time must not be less than 15 minutes. For information on the infusion of Zoledronic acid, see section 6.6.
Patients treated with Zoledronic acid 5 mg/100 ml solution for infusion should be given the package leaflet and the patient reminder card.
4.3 Contraindications
- Hypersensitivity to the active substance, to any bisphosphonates or to any of the
excipients listed in section 6.1.
- Patients with hypocalcaemia (see section 4.4).
- Severe renal impairment with creatinine clearance < 35 ml/min (see section 4.4).
- Pregnancy and breast-feeding (see section 4.6).
4.4 Special warnings and precautions for use
Renal function
The use of zoledronic acid in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population.
Renal impairment has been observed following the administration of zoledronic acid (see section 4.8), especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), or dehydration occurring after zoledronic acid administration. Renal impairment has been observed in patients after a single administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above.
The following precautions should be taken into account to minimise the risk of renal adverse reactions:
• Creatinine clearance should be calculated based on actual body weight using the Cockcroft-Gault formula before each zoledronic acid dose.
• Transient increase in serum creatinine may be greater in patients with underlying impaired renal function.
• Monitoring of serum creatinine should be considered in at-risk patients.
• Zoledronic acid should be used with caution when concomitantly used with other medicinal products that could impact renal function (see section 4.5).
• Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately hydrated prior to administration of zoledronic acid.
• A single dose of zoledronic acid should not exceed 5 mg and the duration of infusion should be at least 15 minutes (see section 4.2).
Hypocalcaemia
Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with zoledronic acid (see section 4.3). Other disturbances of mineral metabolism must also be effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients.
Elevated bone turnover is a characteristic of Paget’s disease of the bone. Due to the rapid onset of effect of zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, may develop and is usually maximal within the first 10 days after infusion of zoledronic acid (see section 4.8).
Adequate calcium and vitamin D intake are recommended in association with Zoledronic acid administration. In addition, in patients with Paget's disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following zoledronic acid administration (see section 4.2).
Patients should be informed about symptoms of hypocalcaemia and receive adequate clinical monitoring during the period of risk. Measurement of serum calcium before infusion of zoledronic acid is recommended for patients with Paget's disease.
Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including zoledronic acid (see section 4.8).
Osteonecrosis of the jaw (ONJ)
ONJ has been reported in the post-marketing setting in patients receiving zoledronic acid for osteoporosis (see section 4.8).
The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with zoledronic acid in patients with concomitant risk factors.
The following should be considered when evaluating a patient’s risk of developing ONJ:
- Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.
- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.
- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.
- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures, e.g. tooth extractions.
All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, non-healing of sores or discharge during treatment with zoledronic acid. While on treatment, invasive dental procedures should be performed with caution and avoided in close proximity to zoledronic acid treatment.
The management plan for patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of zoledronic acid treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.
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.
General
The incidence of post-dose symptoms occurring within the first three days after administration of zoledronic acid can be reduced with the administration of paracetamol or ibuprofen shortly following zoledronic acid administration.
Other products containing zoledronic acid as an active substance are available for oncology indications. Patient being treated with Zoledronic acid 5 mg/100 ml solution for infusion should not be treated with such products or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.
Zoledronic acid 5 mg/100 ml solution for infusion contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per infusion, i.e.
essentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies with other medicinal products have been performed. Zoledronic acid is not systemically metabolised and does not affect human cytochrome P450 enzymes in vitro (see section 5.2). Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and interactions resulting from displacement of highly protein-bound medicinal products are therefore unlikely.
Zoledronic acid is eliminated by renal excretion. Caution is indicated when zoledronic acid is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration) (see section 4.4).
In patients with renal impairment, the systemic exposure to concomitant medicinal products that are primarily excreted via the kidney may increase.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Zoledronic acid is not recommended in women of childbearing potential.
Pregnancy
Zoledronic acid is contraindicated during pregnancy (see section 4.3). There are no adequate data on the use of zoledronic acid in pregnant women. Studies in animals with zoledronic acid have shown reproductive toxicological effects including malformations (see section 5.3). The potential risk for humans is unknown.
Breast-feeding
Zoledronic acid is contraindicated during breast-feeding (see section 4.3). It is unknown whether zoledronic acid is excreted into human milk.
Fertility
Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 generation. This resulted in exaggerated pharmacological effects considered related to the compound’s inhibition of skeletal calcium mobilisation, resulting in periparturient hypocalcaemia, a bisphosphonate class effect, dystocia and early termination of the study. Thus these results precluded determining a definitive effect of zoledronic acid on fertility in humans.
4.7 Effects on ability to drive and use machines
Adverse reactions, such as dizziness, may affect the ability to drive or use machines.
4.8 Undesirable effects Summary of the safety profile
The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and
10.2% after the first, second and third infusion, respectively. Incidence of individual adverse reactions following the first infusion was: pyrexia (17.1%), myalgia (7.8%), influenza-like illness (6.7%), arthralgia (4.8%) and headache (5.1%). The incidence of these reactions decreased markedly with subsequent annual doses of zoledronic acid. The majority of these reactions occur within the first three days following zoledronic acid administration. The majority of these reactions were mild to moderate and resolved within three days of the event onset. The percentage of patients who experienced adverse reactions was lower in a smaller study (19.5%, 10.4%, 10.7% after the first, second and third infusion, respectively), where prophylaxis against adverse reactions was used.
Tabulated list of adverse reactions
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1
|
Infections and infestations |
Uncommon |
Influenza, nasopharyngitis |
|
Blood and lymphatic system disorders |
Uncommon |
Anaemia |
|
Immune system disorders |
Not known** |
Hypersensitivity reactions including rare cases of bronchospasm, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock |
|
Metabolism and nutrition |
Common |
Hypocalcaemia* |
|
disorders |
Uncommon |
Decreased appetite |
|
Psychiatric disorders |
Uncommon |
Insomnia |
|
Nervous system disorders |
Common Uncommon |
Headache, dizziness Lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia |
|
Eye disorders |
Common Uncommon Rare Not known** |
Ocular hyperaemia Conjunctivitis, eye pain Uveitis, episcleritis, iritis Scleritis and parophthalmia |
|
Ear and labyrinth disorders |
Uncommon |
Vertigo |
|
Cardiac disorders |
Common Uncommon |
Atrial fibrillation Palpitations |
|
Vascular disorders |
Uncommon Not known** |
Hypertension, flushing Hypotension (some of the patients had underlying risk factors) |
|
Respiratory, thoracic and mediastinal disorders |
Uncommon |
Cough, dyspnoea |
|
Gastrointestinal disorders |
Common Uncommon |
Nausea, vomiting, diarrhoea Dyspepsia, abdominal pain upper, abdominal pain, gastroesophageal reflux disease, constipation, dry mouth, oesophagitis, toothache, gastritis# |
|
Skin and subcutaneous tissue disorders |
Uncommon |
Rash, hyperhidrosis, pruritus, erythema |
|
Musculoskeletal and connective tissue disorders |
Common Uncommon Rare Very rare Not known** |
Myalgia, arthralgia, bone pain, back pain, pain in extremity Neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, shoulder pain, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness Atypical subtrochanteric and diaphyseal femoral fractures f(bisphosphonate class adverse reaction) Osteonecrosis of the external auditory canalf(bisphosphonate class adverse reaction) Osteonecrosis of the jaw (see sections 4.4 and 4.8 Class effects) |
|
Renal and urinary disorders |
Uncommon |
Blood creatinine increased, pollakiuria, proteinuria |
|
Not known** |
Renal impairment. Rare cases of renal failure requiring dialysis and rare cases with a fatal outcome have been reported in patients with pre-existing renal dysfunction or other risk factors such as advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, or dehydration in the post infusion period (see sections 4.4 and 4.8 Class effects) | |
|
General disorders and |
Very common |
Pyrexia |
|
administration site conditions |
Common |
Influenza-like illness, chills, fatigue, asthenia, pain, malaise, infusion site reaction |
|
Uncommon |
Peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain | |
|
Not known** |
Dehydration secondary to post-dose symptoms such as pyrexia, vomiting and diarrhoea | |
|
Investigations |
Common |
C-reactive protein increased |
|
Uncommon |
Blood calcium decreased |
#
*
**
Observed in patients taking concomitant glucocorticosteroids.
Common in Paget’s disease only.
Based on post-marketing reports. Frequency cannot be estimated from available data.
f Identified in post-marketing experience.
Description of selected adverse reactions Atrial Fibrillation
In the HORIZON - Pivotal Fracture Trial [PFT] (see section 5.1), 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 and placebo, respectively. The rate of atrial fibrillation serious adverse events was increased in patients receiving zoledronic acid (1.3%) (51 out of 3,862) compared with patients receiving placebo (0.6%) (22 out of 3,852). The mechanism behind the increased incidence of atrial fibrillation is unknown. In the osteoporosis trials (PFT, HORIZON - Recurrent Fracture Trial [RFT]) the pooled atrial fibrillation incidences were comparable between zoledronic acid (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events the pooled incidences were 1.3% for zoledronic acid and 0.8% for placebo.
Class effects:
Renal impairment
Zoledronic acid has been associated with renal impairment manifested as deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal dysfunction or additional risk factors (e.g advanced age, oncology patients with chemotherapy, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, severe dehydration), with the majority of them receiving a 4 mg dose every 3-4 weeks, but it has been observed in patients after a single administration.
In clinical trials in osteoporosis, the change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the zoledronic acid and placebo treatment groups over three years. There was a transient increase in serum creatinine observed within 10 days in 1.8% of zoledronic acid -treated patients versus 0.8% of placebo-treated patients.
Hypocalcaemia
In clinical trials in osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 1.87 mmol/l) following zoledronic acid administration. No symptomatic cases of hypocalcaemia were observed.
In the Paget’s disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, in all of whom it resolved.
Based on laboratory assessment, transient asymptomatic calcium levels below the normal reference range (less than 2.10 mmol/l) occurred in 2.3% of zoledronic acid -treated patients in a large clinical trial compared to 21% of zoledronic acid -treated patients in the Paget’s disease trials. The frequency of hypocalcaemia was much lower following subsequent infusions.
All patients received adequate supplementation with vitamin D and calcium in the post- menopausal osteoporosis trial, the prevention of clinical fractures after hip fracture trial, and the Paget’s disease trials (see also section 4.2). In the trial for the prevention of clinical fractures following a recent hip fracture, vitamin D levels were not routinely measured but the majority of patients received a loading dose of vitamin D prior to zoledronic acid administration (see section 4.2).
Local reactions
In a large clinical trial, local reactions at the infusion site, such as redness, swelling and/or pain, were reported (0.7%) following the administration of zoledronic acid.
Osteonecrosis of the jaw
Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, including zoledronic acid (see section 4.4).
In a large clinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one patient treated with zoledronic acid and one patient treated with placebo. Cases of ONJ have been reported in the post-marketing setting for zoledronic acid.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
|
System Organ Class |
Frequency |
MedDRA Term |
|
Infections and infestations |
Uncommon |
Sepsis (immunosuppression), cellulitis at injection site |
|
Not known |
Pneumonia, liver abscess | |
|
Immune system |
Not known |
Anaphylaxis, allergic oedema |
|
Neoplesms benign, malignant and |
Uncommon |
Lentigo |
|
Blood and lymphatic system |
Common |
Anaemia, megaloblastosis, leucopenia, thrombocytop enia |
|
Metabolism and nutrition |
Common |
Anorexia, hyperuricaemia |
|
Nervdus system disorders |
Common |
At high doses cerebellar or cerebral influence with deterioration of the level of consciousness, dysarthria, nystagmus |
|
Uncommon |
hHeadache, peripheral neuropathy and paraplegia at intrathecal administration | |
|
Not known |
Dizziness, neuritis, neural toxicity | |
|
Eye disorders |
Common |
Reversible haemorrhagic conjunctivitis (photophobia, burning, visual disturbance, increased lacrimation), keratitis, conjunctivitis (may occur with rash) |
|
Cardiac disorders |
Uncommon |
Pericarditis |
|
Very rare |
Arrhythmia | |
|
Vascular |
Not known |
Thrombophlebitis |
|
Respiratory, thoracic and |
Uncommon |
Shortness of breath, sore throat |
|
Gartsointestinal disorders |
Common |
Dysphagia, abdominal pain, nausea, vomiting, diarrhoea, oral / anal inflammation or ulceration |
|
Uncommon |
Esophagitis, esophageal ulceration, pneumatosis cystoides intestinalis, necrotising colitis, peritonitis | |
|
Not known |
Pancreatitis, gastrointestinal necrosis | |
|
Hepatobiliary disorders |
Common |
Reversible effects on the liver with increased enzyme levels |
|
Not known |
Hepatic dysfunction, jaundice | |
|
Skin and subcutaneous tissue disorders |
Common |
Reversible undesirable effects to the skin, such as erythema, bullous dermatitis, urticaria, vasculitis, alopecia |
|
Uncommon |
Skin ulceration, pruritus, burning pain of palms and soles | |
|
Very rare |
Neutrophilic eccrine hidradenitis | |
|
Not known |
Freckling, rash |
|
Musculoskeletal and |
Uncommon |
Myalgia, arthralgia |
|
Renal and urinary |
Common |
Renal dysfunction, urinary retention |
|
General disorders and administrat ion site conditions |
Common |
Fever, thrombophlebitis at the injection site |
|
Not known |
Chest pain and injection site reaction (pain and inflammation at the subcutaneous injection sites) | |
|
Investigati ons |
Not known |
Reduced reticulocytes, cellular changes in the morphology of bone marrow and peripheral smears |
Cytarabine (Ara-C) Syndrome: (Immunoallergic effect):
Fever, malaise, myalgia, occasional chest pain, exanthema, conjuctivitis and nausea may occur 6-12 h after start of therapy. Corticosteroids may be considered as prophylaxis and therapy. If they are effective, therapy with cytarabine may be continued.
After Intrathecal use
Nervous system disorders
The risk of CNS toxicity increases if the cytarabine treatment - given as high dose i.v. or intrathecally - is combined with another CNS toxic treatment such as radiation therapy, high dose or intrathecal methotrexate or when given intrathecally in short intervals or in doses above 30 mg/m2
Necrotising leukencephalopathy, bone marrow depression, myelopathy resulting in para- or quadriplegia, paralysis and other isolated neurotoxicities have been reported.
Eye disorders Blindness.
Gastrointestinal disorders
Nausea, vomiting.
General disorders and administration site conditions
Headache, fever and/or other symptoms of an arachnoiditis.
Adverse effects due to high dose cytarabine treatment, other than those seen with conventional doses include:
Infections and infestations:
Sepsis, liver abscess
Hematological toxicity
Seen as profound pancytopenia which may last 15-25 days along with more severe bone marrow aplasia than that observed at conventional doses.
Nervous system disorders
After treatment with high doses of cytarabine, symptoms of cerebral or cerebellar influence like personality changes, affected alertness, dysarthria, ataxia, tremor, nystagmus, headache, confusion, somnolence, dizziness, coma, convulsions, peripheral motor and sensory neuropathies appear in 8-37 % of treated patients. The incidence in elderly (>55 years) may be even higher. Other predisposing factors are impaired liver and renal function, previous CNS treatment (e.g., radiotherapy) and alcohol abuse. CNS disturbances are in the most cases reversible.
The risk of CNS toxicity increases if the cytarabine treatment - given as high dose i.v.- combined with another CNS toxic treatment such as radiation therapy or high dose.
Corneal and conjunctival toxicity:
Reversible lesion of corneal and haemorrhagic conjunctivitis have been described. These phenomena can be prevented or decreased by installation of corticosteroid eye drops.
Respiratory, thoracic and mediastinal disorders
Clinical signs as present in pulmonary oedema/ARDS (adult respiratory distress syndrome) may develop, particularly in high-dose therapy. The reaction is probably caused by an alveolar capillary injury. It is difficult to make an assessment of frequencies (stated as 10-26 % in different publications), since the patients usually have been in relapse where other factors may contribute to this reaction.
A diffuse interstitial pneumonitis without clear cause that may have been related to cytarabine was reported in patients treated with experimental intermediate doses of cytarabine (1g/m2) with and without other chemotherapeutic agents (meta-AMSA, daunorubicin, VP-16).
A syndrome of sudden respiratory distress, rapidly progressing to pulmonary oedema and a radiographically pronounced cardiomegaly has been reported following experimental high dose therapy with cytarabine used for the treatment of relapsed leukemia; fatal outcome has been reported.
Gastrointestinal disorders:
Gastrointestinal necrosis, necrotizing colitis, gastrointestinal ulceration (including pneumatosis cystoides intestinalis leading to peritonitis). Especially in treatment with high doses of cytarabine, more severe reactions may appear in addition to common symptoms. Intestinal perforation or necrosis with ileus and peritonitis have been reported.
Hepatobiliary disorders:
Liver damage with increased hyperbilirubinemia hepatomegaly, Budd-Chiari-syndrome (hepatic venous thrombosis) and pancreatitis have been observed after high-dose therapy.
Skin and subcutaneous tissue disorders:
Skin rash leading to desquamation, alopecia.
Respiratory, thoracic and mediastinal disorders:
Clinical signs as present in pulmonary oedema/ARDS may develop, particularly in high-dose therapy. The reaction is probably caused by an alveolar capillary injury. It is difficult to make an assessment of frequencies (stated as 10-26 % in different publications), since the patients usually have been in relapse where other factors may contribute to this reaction.
Others:
Following cytarabine therapy, cardiomyopathy with subsequent death and rhabdomyolysis have been reported. One case of anaphylaxis that resulted in cardiopulmonary arrest and required resuscitation has been reported. This occurred immediately after the intravenous administration of cytarabine.
The gastro-intestinal undesirable effects are reduced if cytarabine is administered as infusion. Local glucocorticoides are recommended as prophylaxis of haemorrhagic conjunctivitis.
Amenorrhoea and azoospermia (sec section 4.6)
Viral, bacterial, fungal, parasitic, or saprophytic infections, in any location in the body, may be associated with the use of cytarabine alone or in combination with other immunosuppressive agents following immunosuppressant doses that affect cellular or humoral immunity. These infections may be mild, but can be severe and at times fatal.
A Cytarabine syndrome has been described. It is characterised by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs 6 - 12 hours following drug administration. Corticosteroids have been shown to be beneficial in treating or preventing this syndrome. If the symptoms of the syndrome are serious enough to warrant treatment, corticosteroids should be contemplated as well as continuation of therapy with cytarabine.
Cases of pancreatitis have been observed with the induction of cytarabine.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Clinical experience with acute overdose is limited. Patients who have received doses higher than those recommended should be carefully monitored. In the event of overdose leading to clinically significant hypocalcaemia, reversal may be achieved with supplemental oral calcium and/or an intravenous infusion of calcium gluconate.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs for treatment of bone diseases, bisphosphonates, ATC code: M05BA08
Mechanism of action
Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.
Pharmacodynamic effects
The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone.
The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The long duration of action of zoledronic acid is attributable to its high binding affinity for the active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bone mineral.
Zoledronic acid treatment rapidly reduced the rate of bone turnover from elevated post- menopausal levels with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks. Thereafter bone markers stabilised within the pre-menopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.
Clinical efficacy in the treatment of post-menopausal osteoporosis (PFT)
The efficacy and safety of zoledronic acid 5 mg once a year for 3 consecutive years were demonstrated in post-menopausal women (7,736 women aged 65-89 years) with either: a femoral neck bone mineral density (BMD) with a T-score < -1.5 and at least two mild or one moderate existing vertebral fracture(s); or a femoral neck BMD T-score < -2.5 with or without evidence of existing vertebral fracture(s). 85% of patients were bisphosphonate-naive. Women who were evaluated for the incidence of vertebral fractures did not receive concomitant osteoporosis therapy, which was allowed for women contributing to the hip and all clinical fracture evaluations. Concomitant osteoporosis therapy included: calcitonin, raloxifene, tamoxifen, hormone replacement therapy, tibolone; but excluded other bisphosphonates. All women received 1,000 to 1,500 mg elemental calcium and 400 to 1,200 IU of vitamin D supplements daily.
Effect on morphometric vertebral fractures
Zoledronic acid significantly decreased the incidence of one or more new vertebral fractures over three years and as early as the one year timepoint (see Table 2).
Table 2 Summary of vertebral fracture efficacy at 12, 24 and 36 months
|
Outcome |
Zoledronic acid (%) |
Placebo (%) |
Absolute reduction in fracture incidence % (CI) |
Relative reduction in fracture incidence % (CI) |
|
At least one new vertebral fracture (0-1 year) |
1.5 |
3.7 |
2.2 (1.4, 3.1) |
60 (43, 72)** |
|
At least one new vertebral fracture (0-2 year) |
2.2 |
7.7 |
5.5 (4.4, 6.6) |
71 (62, 78)** |
|
At least one new vertebral fracture (0-3 year) |
3.3 |
10.9 |
7.6 (6.3, 9.0) |
70 (62, 76)** |
|
** p <0.0001 | ||||
Zoledronic acid -treated patients aged 75 years and older exhibited a 60% reduction in the risk of vertebral fractures compared to placebo patients (p<0.0001).
Effect on hip fractures
Zoledronic acid demonstrated a consistent effect over 3 years, resulting in a 41% reduction in the risk of hip fractures (95% CI, 17% to 58%). The hip fracture event rate was 1.44% for zoledronic acid -treated patients compared to 2.49% for placebo-treated patients. The risk reduction was 51% in bisphosphonate-nai've patients and 42% in patients allowed to take concomitant osteoporosis therapy.
Effect on all clinical fractures
All clinical fractures were verified based on the radiographic and/or clinical evidence. A summary of results is presented in Table 3.
Table 3 Between treatment comparisons of the incidence of key clinical fracture variables over 3 years
|
Outcome |
Zoledronic acid (N=3,875) event rate (%) |
Placebo (N=3,861) event rate (%) |
Absolute reduction in fracture event rate % (CI) |
Relative risk reduction in fracture incidence % (CI) |
|
Any clinical fracture (1) |
8.4 |
12.8 |
4.4 (3.0, 5.8) |
33 (23, 42)** |
|
Clinical vertebral fracture (2) |
0.5 |
2.6 |
2.1 (1.5, 2.7) |
77 (63, 86)** |
|
Non-vertebral fracture (1) |
8.0 |
10.7 |
2.7 (1.4, 4.0) |
25 (13, 36)* |
*p-value <0.001, **p-value <0.0001
(1) Excluding finger, toe and facial fractures
(2) Including clinical thoracic and clinical lumbar vertebral fractures
Effect on bone mineral density (BMD)
Zoledronic acid significantly increased BMD at the lumbar spine, hip, and distal radius relative to treatment with placebo at all timepoints (6, 12, 24 and 36 months). Treatment with zoledronic acid resulted in a 6.7% increase in BMD at the lumbar spine, 6.0% at the total hip, 5.1% at the femoral neck, and 3.2% at the distal radius over 3 years as compared to placebo.
Bone histology
Bone biopsies were obtained from the iliac crest 1 year after the third annual dose in 152 post- menopausal patients with osteoporosis treated with zoledronic acid (N=82) or placebo (N=70). Histomorphometric analysis showed a 63% reduction in bone turnover. In patients treated with zoledronic acid, no osteomalacia, marrow fibrosis or woven bone formation was detected. Tetracycline label was detectable in all but one of 82 biopsies obtained from patients on zoledronic acid. Microcomputed tomography (pCT) analysis demonstrated increased trabecular bone volume and preservation of trabecular bone architecture in patients treated with zoledronic acid compared to placebo.
Bone turnover markers
Bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I collagen (P1NP) and serum beta-C-telopeptides (b-CTx) were evaluated in subsets ranging from 517 to 1,246 patients at periodic intervals throughout the study. Treatment with a 5 mg annual dose of zoledronic acid significantly reduced BSAP by 30% relative to baseline at 12 months which was sustained at 28% below baseline levels at 36 months. P1NP was significantly reduced by 61% below baseline levels at 12 months and was sustained at 52% below baseline levels at 36 months. B-CTx was significantly reduced by 61% below baseline levels at 12 months and was sustained at 55% below baseline levels at 36 months.
During this entire time period bone turnover markers were within the premenopausal range at the end of each year. Repeat dosing did not lead to further reduction of bone turnover markers.
Effect on height
In the three-year osteoporosis study standing height was measured annually using a stadiometer. The zoledronic acid group revealed approximately 2.5 mm less height loss compared to placebo (95% CI: 1.6 mm, 3.5 mm) [p<0.0001].
Days of disability
Zoledronic acid significantly reduced the mean days of limited activity and the days of bed rest due to back pain by 17.9 days and 11.3 days respectively compared to placebo and significantly reduced the mean days of limited activity and the days of bed rest due to fractures by 2.9 days and 0.5 days respectively compared to placebo (all p<0.01).
Clinicalefficacy inthe treatmentofosteoporosisinpatientsatincreasedriskoffractureafter a recent hipfracture (RFT)
The incidence of clinical fractures, including vertebral, non-vertebral and hip fractures, was evaluated in 2,127 men and women aged 50-95 years (mean age 74.5 years) with a recent (within 90 days) low- trauma hip fracture who were followed for an average of 2 years on study treatment (zoledronic acid). Approximately 42% of patients had a femoral neck BMD T-score below -2.5 and approximately 45% of the patients had a femoral neck BMD T-score above -2.5. Zoledronic acid was administered once a year, until at least 211 patients in the study population had confirmed clinical fractures. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 IU orally or via the intramuscular route) was given to the majority of patients 2 weeks prior to infusion. All participants received 1,000 to 1,500 mg of elemental calcium plus 800 to 1,200 IU of vitamin D supplementation per day. Ninety-five percent of the patients received their infusion two or more weeks after the hip fracture repair and the median timing of infusion was approximately six weeks after the hip fracture repair. The primary efficacy variable was the incidence of clinical fractures over the duration of the study.
Effect on all clinical fractures
The incidence rates of key clinical fracture variables are presented in Table 4.
Table 4 Between treatment comparisons of the incidence of key clinical fracture variables
|
Outcome |
Zoledronic acid (N=1,065) event rate (%) |
Placebo (N=1,062) event rate (%) |
Absolute reduction in fracture event rate % (CI) |
Relative risk reduction in fracture incidence % (CI) |
|
Any clinical fracture (1) |
8.6 |
13.9 |
5.3 (2.3, 8.3) |
35 (16, 50)** |
|
Clinical vertebral fracture (2) |
1.7 |
3.8 |
2.1 (0.5, 3.7) |
46 (8, 68)* |
|
Non-vertebral fracture (1) |
7.6 |
10.7 |
3.1 (0.3, 5.9) |
27 (2, 45)* |
*p-value <0.05, **p-value <0.01
(1) Excluding finger, toe and facial fractures
(2) Including clinical thoracic and clinical lumbar vertebral fractures
The study was not designed to measure significant differences in hip fracture, but a trend was seen towards reduction in new hip fractures.
All cause mortality was 10% (101 patients) in the zoledronic acid-treated group compared to 13% (141 patients) in the placebo group. This corresponds to a 28% reduction in the risk of all cause mortality (p=0.01).
The incidence of delayed hip fracture healing was comparable between zoledronic acid (34 [3.2%]) and placebo (29 [2.7%]).
Effect on bone mineral density (BMD)
In the HORIZON-RFT study zoledronic acid treatment significantly increased BMD at the total hip and femoral neck relative to treatment with placebo at all timepoints. Treatment with zoledronic acid resulted in an increase in BMD of 5.4% at the total hip and 4.3% at the femoral neck over 24 months as compared to placebo.
Clinical efficacy in men
In the HORIZON-RFT study 508 men were randomised into the study and 185 patients had BMD assessed at 24 months. At 24 months a similar significant increase of 3.6% in total hip BMD was observed for patients treated with zoledronic acid as compared to the effects observed in post-menopausal women in the HORIZON-PFT study. The study was not powered to show a reduction in clinical fractures in men; the incidence of clinical fractures was 7.5% in men treated with zoledronic acid versus 8.7% for placebo.
In another study in men (study CZOL446M2308) an annual infusion of zoledronic acid was non-inferior to weekly alendronate for the percentage change in lumbar spine BMD at month 24 relative to baseline.
Clinical efficacy in osteoporosis associated with long-term systemic glucocorticoid therapy.
The efficacy and safety of zoledronic acid in the treatment and prevention of osteoporosis associated with long-term systemic glucocorticoid therapy were assessed in a randomised, multicentre, double-blind, stratified, active-controlled study of 833 men and women aged 18-85 years (mean age for men 56.4 years; for women 53.5 years) treated with > 7.5 mg/day oral prednisone (or equivalent). Patients were stratified with respect to duration of glucocorticoid use prior to randomisation (< 3 months versus > 3 months). The duration of the trial was one year. Patients were randomised to either zoledronic acid 5 mg single infusion or to oral risedronate 5 mg daily for one year. All participants received 1,000 mg elemental calcium plus 400 to 1,000 IU vitamin D supplementation per day. Efficacy was demonstrated if non-inferiority to risedronate was shown sequentially with respect to the percentage change in lumbar spine BMD at 12 months relative to baseline in the treatment and prevention subpopulations, respectively. The majority of patients continued to receive glucocorticoids for the one year duration of the trial.
Effect on bone mineral density (BMD)
The increases in BMD were significantly greater in the zoledronic acid-treated group at the lumbar spine and femoral neck at 12 months compared to risedronate (all p<0.03). In the subpopulation of patients receiving glucocorticoids for more than 3 months prior to randomisation, zoledronic acid increased lumbar spine BMD by 4.06% versus 2.71% for risedronate (mean difference: 1.36% ; p<0.001). In the subpopulation of patients that had received glucocorticoids for 3 months or less prior to randomisation, zoledronic acid increased lumbar spine BMD by 2.60% versus 0.64% for risedronate (mean difference: 1.96% ; p<0.001). The study was not powered to show a reduction in clinical fractures compared to risedronate. The incidence of fractures was 8 for zoledronic acid-treated patients versus 7 for risedronate-treated patients (p=0.8055).
Clinical efficacy in the treatment of Paget’s disease of the bone Zoledronic acid was studied in male and female patients aged above 30 years with primarily mild to moderate Paget’s disease of the bone (median serum alkaline phosphatase level 2.6-3.0 times the upper limit of the age-specific normal reference range at the time of study entry) confirmed by radiographic evidence.
The efficacy of one infusion of 5 mg zoledronic acid versus daily doses of 30 mg risedronate for 2 months was demonstrated in two 6-month comparative trials. After 6 months, zoledronic acid showed 96% (169/176) and 89% (156/176) response and serum alkaline phosphatase (SAP) normalisation rates compared to 74% (127/171) and 58% (99/171) for risedronate (all p<0.001).
In the pooled results, a similar decrease in pain severity and pain interference scores relative to baseline were observed over 6 months for zoledronic acid and risedronate.
Patients who were classified as responders at the end of the 6 month core study were eligible to enter an extended follow-up period. Of the 153 zoledronic acid-treated patients and 115 risedronate-treated patients who entered an extended observation study, after a mean duration of follow-up of 3.8 years from time of dosing, the proportion of patients ending the Extended Observation Period due to the need for retreatment (clinical judgment) was higher for risedronate (48 patients, or 41.7%) compared with zoledronic acid (11 patients, or 7.2%). The mean time of ending the Extended Observation Period due to the need for Paget’s re-treatment from the initial dose was longer for zoledronic acid (7.7 years) than for risedronate (5.1 years).
Six patients who achieved therapeutic response 6 months after treatment with Zoledronic acid and later experienced disease relapse during the extended follow-up period were re- treated with zoledronic acid after a mean time of 6.5 years from initial treatment to re- treatment. Five of the 6 patients had SAP within the normal range at month 6 (Last Observation Carried Forward, LOCF).
Bone histology was evaluated in 7 patients with Paget’s disease 6 months after treatment with 5 mg zoledronic acid. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodelling and no evidence of mineralisation defects. These results were consistent with biochemical marker evidence of normalisation of bone turnover.
5.2 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.
Distribution
After initiation of the zoledronic acid infusion, plasma concentrations of the active substance increased rapidly, 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 levels.
Elimination
Intravenously administered zoledronic acid is eliminated by a triphasic process: rapid biphasic disappearance from the systemic circulation, with half-lives of ti/2(1 0.24 and ti/2 p 1.87 hours, followed by a long elimination phase with a terminal elimination half-life of t/2 y 146 hours.
There was no accumulation of the active substance in plasma after multiple doses given every 28 days. The early disposition phases (a and P, with t/ values above) presumably represent rapid uptake into bone and excretion via the kidneys.
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. This uptake into bone is common for all bisphosphonates and is presumably a consequence of the structural analogy to pyrophosphate. As with other bisphosphonates, the retention time of zoledronic acid in bones is very long. 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 or body weight. The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively. 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.
Pharmacokinetic/pharmacodynamic relationships
No interaction studies with other medicinal products have been performed with zoledronic acid. Since zoledronic acid is not metabolised in humans and the substance was found to have little or no capacity as a direct-acting and/or irreversible metabolism-dependent inhibitor of P450 enzymes, zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolised via the cytochrome P450 enzyme systems. Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and binding is concentration independent. Therefore, interactions resulting from displacement of highly protein-bound medicinal products are unlikely.
Special populations (see section 4.2)
Renal impairment
The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 75 ±33% of the creatinine clearance, which showed a mean of 84 ± 29 ml/min (range 22 to 143 ml/min) in the 64 patients studied. Small observed increases in AUC(0.24hr), by about 30% to 40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Clcr = 50-80 ml/min) and moderate renal impairment down to a creatinine clearance of 35 ml/min are not necessary. The use of zoledronic acid in patients with severe renal impairment (creatinine clearance <35 ml/min) is contraindicated due to an increased risk of renal failure in this population.
5.3 Preclinical safety data
Acute toxicity
The highest non-lethal single intravenous dose was 10 mg/kg body weight in mice and 0.6 mg/kg in rats. In the single-dose dog infusion studies, 1.0 mg/kg (6 fold the recommended human therapeutic exposure based on AUC) administered over 15 minutes was well tolerated with no renal effects.
Subchronic and chronic toxicity
In the intravenous infusion studies, renal tolerability of zoledronic acid was established in rats when given 0.6 mg/kg as 15-minute infusions at 3-day intervals, six times in total (for a cumulative dose that corresponded to AUC levels about 6 times the human therapeutic exposure) while five 15-minute infusions of 0.25 mg/kg administered at 2-3-week intervals (a cumulative dose that corresponded to 7 times the human therapeutic exposure) were well tolerated in dogs. In the intravenous bolus studies, the doses that were well-tolerated decreased with increasing study duration: 0.2 and 0.02 mg/kg daily was well tolerated for 4 weeks in rats and dogs, respectively but only 0.01 mg/kg and 0.005 mg/kg in rats and dogs, respectively, when given for 52 weeks.
Longer-term repeat administration at cumulative exposures sufficiently exceeding the maximum intended human exposure produced toxicological effects in other organs, including the gastrointestinal tract and liver, and at the site of intravenous administration. The clinical relevance of these findings is unknown. The most frequent finding in the repeat-dose studies consisted of increased primary spongiosa in the metaphyses of long bones in growing animals at nearly all doses, a finding that reflected the compound’s pharmacological antiresorptive activity.
Reproduction toxicity
Teratology studies were performed in two species, both via subcutaneous administration. Teratogenicity was observed in rats at doses > 0.2 mg/kg and was manifested by external, visceral and skeletal malformations. Dystocia was observed at the lowest dose (0.01 mg/kg body weight) tested in rats. No teratological or embryo/foetal effects were observed in rabbits, although maternal toxicity was marked at 0.1 mg/kg due to decreased serum calcium levels.
Mutagenicity and carcinogenic potential
Zoledronic acid was not mutagenic in the mutagenicity tests performed and carcinogenicity testing did not provide any evidence of carcinogenic potential.
6.1 List of excipients
Mannitol
Sodium citrate anhydrous Water for injections
6.2 Incompatibilities
Mannitol
Sodium citrate anhydrous Water for injections
6.3 Shelf life
Unopened vial: 2 years
After first opening, the product should be used immediately. Discard any unused contents.
6.4 Special precautions for storage
Store below 30°C.
For storage conditions after first opening of the medicinal product, please see section 6.3.
6.5 Nature and contents of container
100 ml solution in a Type 1 moulded glass vial with a grey bromobutyl omniflex-plus coated rubber closure and flip off aluminum seal.
Zoledronic acid is supplied in packs containing one vial as unit pack or in multipacks comprising 5 packs, each containing 1 vial.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
For single use only.
Any unused product or waste material should be disposed of in accordance with local requirements. Only clear solution free from particles and discoloration should be used.
If refrigerated, allow the refrigerated solution to reach room temperature before administration. Aseptic techniques must be followed during the preparation of the infusion.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL, UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/1558
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
12/12/2013
10 DATE OF REVISION OF THE TEXT
21/12/2015