Zoledronic acid Mylan 4mg/ 5ml concentrate for solution for infusion

4.2. Posology and method of administration

Posology
Prevention of skeletal related events in patients with advanced malignancies involving bone
Adults and olderelderly people

Treatment of TIH
Adults and olderelderly people

4.4. Special warnings and precautions for use

General

Zoledronic acid Mylan contains the same active substance as found in medicinal products indicated for treatment of osteoporosis and Paget´s disease of the bone. Patients being treated with Zoledronic acid Mylan should not be treated with such medicinal products or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown.

Osteonecrosis
Osteonecrosis of the jaw


5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Drugs affecting bone structure and mineralizationfor treatment of bone diseases, bisphosphonates, ATC code: M05BA08

In addition to being a potent inhibitor of bone resorption, zoledronic acid also possesses several anti tumour properties that could contribute to its overall efficacy in the treatment of metastatic bone disease. The following properties have been demonstrated in preclinical studies:
- 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 drugsmedicinal products, anti adhesion/invasion activity.


Table 2, 3 & 4- zoledronic changed to Zoledronic on all tables

The type of adverse reactions observed in this population were similar to those previously seen in adults with advanced malignancies involving the bone (see section 4.8). The adverse reactions ranked under headings of frequency, are presented in Table 6. The following conventional classification is used:
Vvery common (≥ 1/10),
c Common (≥ 1/100 to < 1/10),
u Uncommon (≥ 1/1,000 to < 1/100),
r Rare (≥ 1/10,000 to < 1/1,000),
v Very rare (< 1/10,000),
n Not known (cannot be estimated from the available data).

6. PHARMACEUTICAL PARTICULARS

6.2. Incompatibilities

Zoledronic acid Mylan concentrateThis medicinal product must not be mixed with calcium or other divalent cation containing infusion solutions such as lactated Ringer’s solution, and should be administered as a single intravenous solution in a separate infusion line.

6.3. Shelf life

2 years.

After dilution: Chemical and physical in use stability has been demonstrated for 48 hours at 2°C 8°C and at 25°C after dilution in 100 ml sodium chloride 9 mg/ml (0.9%) solution for injection or 5% w/v glucose solution (minimal concentration: 3 mg/100 ml; maximal concentration: 4 mg/100 ml).
From a microbiological point of view, the product 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, unless dilution has taken place in controlled and validated aseptic conditions. The refrigerated solution should then be equilibrated to room temperature prior to administration.

6.4. Special precautions for storage

No special precautions for storage.This medicinal product does not require any special storage conditions.
If refrigerated, the solution must be allowed to reach room temperature before administration.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5. Nature and contents of container

15 ml colourless type I glass vial with a bromobutyl rubber stopper and an aluminium crimp cap with plastic flip off component.
Each vial contains 5 ml of concentrate.

Packs containing 1, 4 or 10 vials or multipacks containing 4 (4 packscartons of 1) vials.

Not all pack sizes may be marketed.

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 23.08.2012
Date of latest renewal:

 4.8.    Undesirable effects

Blood and lymphatic system disorders
Common:	Anaemia
Uncommon:	Thrombocytopenia, leukopenia
Rare:	Pancytopenia
Immune system disorders
Uncommon:	Hypersensitivity reaction
Rare:	Angioneurotic oedema
Psychiatric disorders
Uncommon:	Anxiety, sleep disturbance
Rare:	Confusion
Nervous system disorders
Common:	Headache
Uncommon:	Dizziness, paraesthesia, dysgeusia, hypoaesthesia, hyperaesthesia, tremor, somnolence
Very rare:	Convulsions, hypoaesthesia and tetany (secondary to hypocalcaemia)
Eye disorders
Common:	Conjunctivitis
Uncommon:	Blurred vision, scleritis and orbital inflammation
Rare:	Uveitis
Very rare:	Episcleritis
Cardiac disorders
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:	Dyspnoea, cough, bronchoconstriction
Rare:	Interstitial lung disease
Gastrointestinal disorders
Common:	Nausea, vomiting, decreased appetite
Uncommon:	Diarrhoea, 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, generalised pain
Uncommon:	Muscle spasms, osteonecrosis of the jaw
Very rare:	Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)
Renal and urinary disorders
Common:	Renal impairment
Uncommon:	Acute renal failure, haematuria, proteinuria
Rare:	Acquired Fanconi syndrome
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
Rare:	Arthritis and joint swelling as a symptom of acute phase reaction
Investigations
Very common:	Hypophosphataemia
Common:	Blood creatinine and blood urea increased, hypocalcaemia
Uncommon:	Hypomagnesaemia, hypokalaemia
Rare:	Hyperkalaemia, hypernatraemia

4.2. Posology and method of administration

 

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

 

 

Patients treated with Zoledronic acid Mylan should be given the package leaflet and the patient reminder card.

 

 

4.4. Special warnings and precautions for use

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported

uncommonly in clinical trials and in the post marketing setting in patients receiving zoledronic acid, predominantly those with cancer, receiving treatment with medicinal products that inhibit bone resorption, such as zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis.

 

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, except in medical emergency situations. A dental examination with appropriate preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with bisphosphonates in patients with concomitant risk factors.

 

 

 

The following risk factors should be considered when evaluating an individual’s risk of developing ONJ:

- Potency of the bisphosphonate (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose 

of bisphosphonate.

 

 

 

-

 

Cancer, co morbid conditions (e.g. anaemia, coagulopathies, infection), smoking. 

 

 

 

-

Concomitant therapies: chemotherapy (see section 4.5), angiogenesis inhibitors (see section 4.5), radiotherapy to neck and head, corticosteroids, smoking.  

 

 

 

- History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures

 

(e.g. tooth extractions) and poorly fitting dentures.

 

A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors. 

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, or non-healing of sores or discharge during treatment with Zoledronic acid Mylan.

 

 

 

While on treatment,

these patients should avoid invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to zoledronic acid administration if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw.

Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. 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.

 

 

 

4.8. Undesirable effects

 

Osteonecrosis of the jaw

 

 

Cases of osteonecrosis (primarily of the jaws) have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as zoledronic acid (see section 4.4). Many of these patients were also receiving chemotherapy and corticosteroids and had signs of local infection including osteomyelitis., and tThe majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaws has multiple documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing oral disease). Although causality has not been determined, it is recommended to avoid dental surgery as recovery may be prolonged (see section 4.4).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Section 4.4
Text added: 

Caution is advised when zoledronic acid 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 must be corrected before initiating zoledronic acid therapy. Patients should be adequately supplemented with calcium and vitamin D.

Section 4.5
Underlined text added
Caution is advised when bisphosphonates are administered with aminoglycosides, calcitonin or loop diuretics, since these agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required (see section 4.4).

Section 4.6
Text Added

Women of child-bearing potential should be advised to avoid becoming pregnant.

Section 4.8
Underlined text added
The following are the important identified risks with zoledronic acid in the approved indications:
Renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, ocular adverse events, atrial fibrillation, anaphylaxis, interstitial lung disease. The frequencies for each of these identified risks are shown in Table 1.

Nervous System disorder
Uncommon:  taste disturbance, dysgeusia (text added)
Very Rare: Convulsions, hypraesthesia, numbness

Eye disorders
Rare:  Uveitis
Very rare: Uveitis,

Cardiac Disorders:
Rare: cardiac arrhythmia (secondary to hypocalcaemia)
Very Rare: Cardiac arrhythmia (secondary to hypocalcaemia)

Gastrointestinal disorders
Common: anorexia decreased appetite

Musculoskeletal and connective Tissue disorders
Uncommon: cramps spasms

Hypocalcaemia-related ADRs
seizures convulsions, numbness hypoaesthesia

Section 5.2
In an in vitro study, zoledronic acid showed low affinity for the cellular components of human blood, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/ml to 5000 ng/ml. The plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/ml to 77% at 2000 ng/ml of zoledronic acid.



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

 

Posology

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

Adults and elderlyolder 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.

 

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

 

Treatment of TIH

Adults and older peopleelderly

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

 

For instructions on the dilution of the medicinal product Zoledronic acid Mylan before administration, see section 6.6. The withdrawn amount of concentrate must be further diluted in 100 ml of sterile sodium chloride 9 mg/ml (0.9%) solution for injection or 5% w/v glucose solution. The dose must be given as a single intravenous infusion over no less than 15 minutes.

4.8.    Undesirable effects

 

Summary of the safety profile

Within three days after zoledronic acid administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, and rigors and arthritis with subsequent joint swelling; these symptoms usually resolve within a few days (see description of selected adverse reactions).

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
Rare:	Arthritis and joint swelling as a symptom of acute phase reaction

 

Acute phase reaction

This adverse drug reaction consists of a constellation of symptoms that includes fever, myalgia, headache, extremity pain, nausea, vomiting, diarrhoea, and arthralgia and arthritis with subsequent joint swelling. The onset time is ≤ 3 days post‑zoledronic acid infusion, and the reaction is also referred to using the terms “flu‑like” or “post‑dose” symptoms.

 

 

In section 4.2 section 'method of administration' the text 'and section 4.4' has been added
In section 4.4 the following sentence has been removed
'Cases of severe hypocalcaemia requiring hospitalisation have been reported. In some instances, life threatening hypocalcaemia may be encountered'
and the following text has been added

 

Hypocalcaemia

Hypocalcaemia has been reported in patients treated with zoledronic acid. Cardiac arrhythmias and neurologic adverse events (including seizures, numbness and tetany) have been reported secondary to cases of severe hypocalcaemia. Cases of severe hypocalcaemia requiring hospitalisation have been reported. In some instances, the hypocalcaemia may be life-threatening (see section 4.8).

The following text is added to section 4.5

 

 

Caution is advised when zoledronic acid is administered with anti-angiogenic medicinal products as an increase in the incidence of ONJ has been observed in patients treated concomitantly with these medicinal products.

The following text has been added to section 4.8
Under nervous system disorder:  Very rare seizures, numbness and tetany (secondary to hypocalcaemia)
Under cardiac disorders: Very rare Cardiac arrhythmia (secondary to hypocalcaemia)

& the following text 

Hypocalcaemia-related ADRs

Hypocalcaemia is an important identified risk with zoledronic acid in the approved indications. Based on the review of both clinical trial and post-marketing cases, there is sufficient evidence to support an association between zoledronic acid therapy, the reported event of hypocalcaemia, and the secondary development of cardiac arrhythmia. Furthermore, there is evidence of an association between hypocalcaemia and secondary neurological events reported in these cases including; seizures, numbness and tetany (see section 4.4).

 

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 national reporting system listed in Appendix V.

 

 

 

 

 

None provided