ROKFOS I.V. Infusion (Zoledronic acid)

Table of Content

Osteoporosis is a progressive systemic disease resulting in increased bone fragility and susceptibility to fractures at vertebral and non-vertebral sites.

Therapeutic adherence is a key factor influencing the effectiveness of treatment in chronic diseases where the effects of the therapy can only be seen after a long-term application of drugs or are subjectively not perceived at all.

The situation is even more complicated in chronic asymptomatic diseases like hypertension or osteoporosis.

Once yearly dosing with Zoledronic acid is a new alternative in the therapy of osteoporosis and represents an important step towards an improvement in the adherence to treatment.

Cipla introduces ROKFOS, once yearly Zoledronic acid 5 mg for the management of osteoporosis.

ROKFOS is indicated for:

  • Treatment and prevention of post-menopausal osteoporosis.
  • Treatment to increase bone mass in men with osteoporosis.
  • Treatment of Paget's disease of the bone.

The recommended dose is a single intravenous infusion of 5 mg Zoledronic acid administered once a year given over no less than 15 minutes.

January 2019

 

To be sold by retail on the prescription of Registered Medical Practitioner only

1 Generic Name

Zoledronic Acid Infusion

2 Qualitative and Quantitative Composition

Each 100 ml contains:

Zoledronic Acid IP equivalent to

Zoledronic Acid anhydrous …………………….. 5 mg

Water for injection qs to…………………………… 100 mL

3 Dosage Form and Strength

Solution for intravenous infusion containing 5mg zoledronic acid in 100mL

Clear and colourless solution

4 Clinical Particulars

4.1 Therapeutic Indications

  • For the treatment of postmenopausal osteoporosis.
  • For the treatment of osteoporosis in postmenopausal women and in men who are at increased risk of fracture, including those with recent low trauma hip fracture.
  • Prevention of clinical fractures after fracture in men and women.
  • Paget’s disease of the bone.

Important Limitations of Use

The safety and effectiveness parameters of zoledronic acid for the treatment of osteoporosis are based on clinical data of 3 years’ duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low risk for fracture should be considered for drug discontinuation after 3–5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

4.2 Posology and Method of Administration

Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Zoledronic acid solution for infusion must not be allowed to come in contact with any calcium-containing solutions or other divalent cation containing solutions, and should be administered as a single intravenous solution through a separate vented infusion line.

Patients must be appropriately hydrated prior to the administration of ROKFOS. This is especially important for the elderly and for patients receiving diuretic therapy. The intravenous infusion should be followed by a 10 mL normal saline flush of the intravenous line. ROKFOS can be infused without regard to meals.

A 5 mg dose of ROKFOS administered intravenously is recommended for patients with creatinine clearance >35 mL/min.  Zoledronic acid is contraindicated in patients with creatinine clearance <35 mL/min and in those with evidence of acute renal impairment. There is no safety or efficacy data to support the adjustment of the zoledronic acid dose, based on baseline renal function. Therefore, no dose adjustment is required in patients with creatinine clearance >35 mL/min. A routine oral examination should be performed by the prescriber prior to initiation of zoledronic acid treatment.

The incidence of post-dose symptoms occurring within the first 3 days after administration of zoledronic acid can be reduced with the administration of paracetamol or ibuprofen shortly following zoledronic acid administration.

Treatment of Postmenopausal Osteoporosis

The recommended regimen is a single intravenous infusion of 5 mg ROKFOS administered once a year given over no less than 15 minutes. For osteoporosis treatment, and to reduce the risk of hypocalcaemia, patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. Postmenopausal women require an average of at least 1,200 mg of calcium and 800–1,000 IU of vitamin D daily.

Treatment to Increase Bone Mass in Men with Osteoporosis

The recommended regimen is a single intravenous infusion of 5 mg ROKFOS administered once a year given over no less than 15 minutes. Patients must be adequately supplemented with calcium and vitamin D if dietary intake is not sufficient. An average of at least 1,200 mg of calcium and 800–1,000 IU of vitamin D daily is recommended.

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. 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.

Treatment of Paget's disease

ROKFOS should be prescribed only by physicians with experience in the treatment of Paget's disease of the bone. The recommended regimen is a single intravenous infusion of 5 mg ROKFOS given over no less than 15 minutes.

To reduce the risk of hypocalcaemia, all patients should receive 1,500 mg elemental calcium daily in divided doses (750 mg two times a day, or 500 mg three times a day) and 800 IU vitamin D daily, particularly in the 2 weeks following ROKFOS administration. All patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcaemia.

Re-treatment of Paget's disease

Specific re-treatment data are not available. After a single treatment with zoledronic acid in Paget's disease, an extended remission period is observed in responding patients.

However, re-treatment with zoledronic acid may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, or in those patients who failed to achieve normalization of their serum alkaline phosphatase, or in those patients with symptoms, as dictated by medical practice.

4.3 Contraindications 

  • Hypocalcaemia.
  • Zoledronic acid is contraindicated in patients with creatinine clearance <35 ml/min and in those with evidence of acute renal impairment due to an increased risk of renal failure.
  • Hypersensitivity to the active substance or any of the excipients. Hypersensitivity reactions, including rare cases of urticaria, angio-oedema, and anaphylactic reaction/shock, have been reported.
  • Pregnancy and lactation.

4.4 Special Warnings and Precautions for Use

Drug Products with Same Active Ingredient

ROKFOS (Zoledronic acid 5 mg) contains the same active ingredient found in ZOLDRIA (Zoledronic acid 4 mg) from Cipla, used for oncology indications, and a patient being treated with ZOLDRIA should not be treated with ROKFOS.

Hypocalcaemia and Mineral Metabolism

Zoledronic acid may cause hypocalcaemia. Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with zoledronic acid. Pre-existing disturbances of calcium and mineral metabolism (e.g. hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of the small intestine) must be effectively treated before initiating therapy with zoledronic acid, and clinical monitoring of calcium and mineral levels is highly recommended 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. Hypocalcaemia following zoledronic acid administration is a significant risk in Paget’s disease. All patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels, and on the symptoms of hypocalcaemia.

All osteoporosis patients should be instructed on the importance of calcium and vitamin D supplementation in maintaining serum calcium levels.

Renal Impairment

A single dose of zoledronic acid should not exceed 5 mg and the duration of infusion should be no less than 15 minutes. Zoledronic acid is contraindicated in patients with creatinine clearance <35 mL/min and in those with evidence of acute renal impairment. If history or physical signs suggest dehydration, zoledronic acid therapy should be withheld until normovolaemic status has been achieved.

Zoledronic acid should be used with caution in patients with chronic renal impairment. Acute renal impairment, including renal failure, has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal compromise, advanced age, concomitant nephrotoxic medications, concomitant diuretic therapy, or severe dehydration occurring before or after zoledronic acid administration. Acute renal failure has been observed in patients after a single administration. Rare reports of hospitalization and/or dialysis or fatal outcome occurred in patients with underlying moderate-to-severe renal impairment or with any of the risk factors described in this section. Renal impairment may lead to increased exposure of concomitant medications and/or their metabolites that are primarily renally excreted.

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 impaired renal function; interim monitoring of creatinine clearance should be performed in at-risk patients. Elderly patients and those receiving diuretic therapy are at increased risk of acute renal failure. These patients should have their fluid status assessed and be appropriately hydrated prior to administration of zoledronic acid. Zoledronic acid should be used with caution with other nephrotoxic drugs. Consider monitoring creatinine clearance in patients at-risk for acute renal failure who are taking concomitant medications that are primarily excreted by the kidneys.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates, including zoledronic acid. Dental surgery may exacerbate the condition. Most cases have been in cancer patients undergoing dental procedures such as tooth extraction. Some cases have occurred in patients with postmenopausal osteoporosis treated with either oral or intravenous bisphosphonates. A routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with a history of concomitant risk factors (e.g. cancer, chemotherapy, angiogenesis inhibitors, radiotherapy, corticosteroids, poor oral hygiene, pre-existing dental disease or infection, anaemia, coagulopathy). The risk of ONJ may increase with duration of exposure to bisphosphonates. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ.

The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions 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, patients with concomitant risk factors should avoid invasive dental procedures if possible. For patients who develop ONJ 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 ONJ. The clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. 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 Subtrochanteric and Diaphyseal Femoral Fractures

Atypical, low-energy or low-trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients, primarily in patients receiving long-term treatment for osteoporosis. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Poor healing of these fractures has also been reported. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Acute Phase Reactions

Acute phase reactions (APRs) or post-dose symptoms such as fever, myalgia, flu-like symptoms, arthralgia and headache have been observed, the majority of which occurred within three days following zoledronic acid administration.

APRs may sometimes be serious or prolonged in duration. The incidence of post-dose symptoms can be reduced with the administration of paracetamol or ibuprofen shortly following zoledronic acid administration. It is also advisable to postpone treatment if the patient is clinically unstable due to an acute medical condition and an APR could be problematic.

Musculoskeletal Pain

In postmarketing experience, severe and, occasionally, incapacitating bone, joint and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including zoledronic acid.

The time to onset of symptoms varied from one day to several months after starting the drug. Consider withholding future zoledronic acid treatment, if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when re-challenged with the same drug or another bisphosphonate.

Patients with Asthma

While not observed in clinical trials with zoledronic acid, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates. Use zoledronic acid with caution in aspirin-sensitive patients.

4.5 Drug Interactions

Aminoglycosides

Caution is advised when bisphosphonates, including zoledronic acid, are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This has not been reported in zoledronic acid clinical trials.

Loop Diuretics

Caution should also be exercised when zoledronic acid is used in combination with loop diuretics due to an increased risk of hypocalcaemia.

Nephrotoxic Drugs

Caution is indicated when zoledronic acid is used with other potentially nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs).

Drugs Primarily Excreted by the Kidneys

Renal impairment has been observed following the administration of zoledronic acid in patients with pre-existing renal compromise or other risk factors. In patients with renal impairment, the exposure to concomitant medications that are primarily renally excreted (e.g. digoxin) may increase. Consider monitoring serum creatinine in patients at risk for renal impairment who are taking concomitant medications that are primarily excreted by the kidneys.

Zoledronic acid is not systemically metabolized and does not affect human CYP450 enzymes in vitro. Zoledronic acid is not highly bound to plasma proteins (approximately 43–55% bound) and interactions resulting from displacement of highly protein-bound drugs are, therefore, unlikely.

4.6 Use in Special Populations

Renal Impairment

Zoledronic acid is contraindicated in patients with creatinine clearance <35 mL/min and in those with evidence of acute renal impairment.

There is no safety or efficacy data to support the adjustment of the zoledronic acid dose based on baseline renal function. Therefore, no dosage adjustment is required in patients with a creatinine clearance of >35 mL/min.

Risk of acute renal failure may increase with underlying renal disease and dehydration secondary to fever, sepsis, gastrointestinal losses, diuretic therapy, advanced age, etc.

Hepatic Impairment

Zoledronic acid is not metabolized in the liver. No clinical data are available for the use of zoledronic acid in patients with hepatic impairment.

Pregnancy

Available data on the use of zoledronic acid in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue Zoledronic Acid when pregnancy is recognized.

Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of years. The amount of bisphosphonate incorporation into adult bone and, hence, available for release into the systemic circulation, is directly related to the dose and duration of bisphosphonate use.  Consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables, such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Lactation 

There are no data on the presence of zoledronic acid in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Zoledronic Acid and any potential adverse effects on the breast-fed child from Zoledronic Acid, or from the underlying maternal condition.

Females and Males of Reproductive Potential

There are no data available in humans. Female fertility may be impaired based on animal studies demonstrating adverse effects of Zoledronic Acid on fertility parameters.

Paediatric Use

Zoledronic acid is not indicated for use in children.

Geriatric Use

Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.

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 

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 overall percentage of patients who reported acute phase reactions or post-dose symptoms (including serious cases) after Zoledronic Acid administration is as follows (frequencies derived from the study in treatment of post-menopausal osteoporosis): fever (18.1%), myalgia (9.4%), flu-like symptoms (7.8%), arthralgia (6.8%) and headache (6.5%), the majority of which occurred within the first 3 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.

The adverse reactions are summarized in the table below according to the 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); and, not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations

Uncommon

Influenza, nasopharyngitis

Blood and lymphatic system disorders

Uncommon

Anaemia

Immune system disorders

Not known**

Hypersensitivity reactions, including rare cases of bronchoconstriction, urticaria and angio-oedema, and very rare cases of anaphylactic reaction/shock

Metabolism and nutrition disorders

Common

Hypocalcaemia*

 

Uncommon

Anorexia, decreased appetite

 

Rare

Hypophosphataemia

Psychiatric disorders

Uncommon

Insomnia

Nervous system disorders

Common

Headache, dizziness, hypoaesthesia

 

Uncommon

Lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia

Eye disorders

Common

Ocular hyperaemia

 

Uncommon

Conjunctivitis, eye pain

 

Rare

Uveitis, episcleritis, iritis

 

Not known**

Scleritis, parophthalmia and orbital inflammation

Ear and labyrinth disorders

Uncommon

Vertigo

Cardiac disorders

Common

Atrial fibrillation

 

Uncommon

Palpitations

Vascular disorders

Uncommon

Hypertension, flushing

 

Not known**

Hypotension (some of the patients had underlying risk factors)

Respiratory, thoracic and mediastinal disorders

Uncommon

Cough, dyspnoea

Gastrointestinal disorders

Common

Nausea, vomiting, diarrhoea

 

Uncommon

Dyspepsia, upper abdominal pain, abdominal pain, gastro-oesophageal reflux disease, constipation, dry mouth, oesophagitis, toothache, gastritis#

Skin and subcutaneous tissue disorders

Uncommon

Rash, hyperhydrosis, pruritus, erythema

Musculoskeletal and connective tissue disorders

Common

Myalgia, arthralgia, bone pain, back pain, pain in extremity, osteoarthritis, joint swelling, flank pain, pain in jaw

 

Uncommon

Neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness

 

Rare

Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate-class adverse reaction)

 

Not known**

ONJ

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

General disorders and administration site conditions

Very common

Fever

Common

Flu-like symptoms, 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 fever, 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 postmarketing reports. Frequency cannot be estimated from available data.

Identified in postmarketing experience.

Description of Selected Adverse Reactions

Atrial Fibrillation

In the reference HORIZON–Pivotal Fracture Trial , 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 reference osteoporosis trials (PFT, HORIZON–Recurrent Fracture Trial ) the pooled atrial fibrillation incidences were comparable between zoledronic acid (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events, the pooled incidence was 1.3% for zoledronic acid and 0.8% for placebo.

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 3 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 reference 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 (<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 reference 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 reference Paget's disease trials. 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.

Local Reactions

In a large reference 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.

ONJ

Cases of ONJ have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, including zoledronic acid. In a large reference clinical trial in 7,736 patients, ONJ has been reported in 1 patient treated with zoledronic acid and 1 patient treated with placebo. Cases of ONJ have been reported in the post-marketing setting for zoledronic acid.

Acute-phase Reactions

Zoledronic acid has been associated with the signs and symptoms of acute-phase reaction, influenza-like illness, pyrexia, myalgia, arthralgia, and bone pain.

Symptoms usually occur within the first 3 days following zoledronic acid administration. One or more of these events which were suspected to be related to the drug were reported in 25% of patients in the zoledronic acid-treated group, compared to 8% in the risedronate-treated group. The majority of these symptoms resolved within 4 days of onset.

Ocular Adverse Events

Cases of iritis/uveitis/episcleritis have been reported in patients treated with bisphosphonates, although no cases were reported in the reference Paget's disease clinical studies. Conjunctivitis has been reported in patients treated with zoledronic acid.

Gastrointestinal Disorders

Nausea, diarrhoea, constipation, dyspepsia, abdominal discomfort, abdominal distension, abdominal pain and vomiting have been reported.

Bronchoconstriction in Aspirin-Sensitive Asthma Patients

While not observed in reference clinical trials, there have been previous reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates.

Post-marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been identified during post-approval use of zoledronic acid infusion:

Acute-phase Reactions

Fever, headache, flu-like symptoms, nausea, vomiting, diarrhoea, arthralgia, and myalgia. Symptoms may be significant and lead to dehydration.

Acute Renal Failure

Acute renal failure requiring hospitalization and/or dialysis or with a fatal outcome have been rarely reported. Increased serum creatinine was reported in patients with 1) underlying renal disease, 2) dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic therapy, or 3) other risk factors such as advanced age, or concomitant nephrotoxic drugs in the post-infusion period. Transient rise in serum creatinine can be correctable with intravenous fluids.

Allergic Reactions

Allergic reactions with intravenous zoledronic acid, including anaphylactic reaction/shock, urticaria, angio-oedema, Stevens-Johnson syndrome, toxic epidermal necrolysis and bronchoconstriction, have been reported.

Asthma Exacerbations

Asthma exacerbations have been reported.

Hypocalcaemia

Hypocalcaemia has been reported.

Hypophosphatemia

Hypophosphatemia has been reported.

ONJ

ONJ has been reported.

Osteonecrosis of other bones

Cases of osteonecrosis of other bones (including femur, hip, knee, ankle, wrist and humerus) have been reported; causality has not been determined in the population treated with zoledronic acid.

Ocular Adverse Events

Cases of the following events have been reported: conjunctivitis, iritis, iridocyclitis, uveitis, episcleritis, scleritis and orbital inflammation/oedema.

Other

Hypotension in patients with underlying risk factors has been reported.

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 18002677779 (Cipla Number) or you can report to PvPI on 1800 180 3024. By reporting side-effects, you can help provide more information on the safety of this product.

4.9 Overdose

There is limited experience of acute overdose with zoledronic acid injection. Patients who have received doses higher than those recommended should be carefully monitored. Overdosage may cause clinically significant renal impairment, hypocalcaemia, hypophosphataemia, and hypomagnesaemia. Clinically relevant reductions in serum levels of calcium, phosphorus and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulphate, respectively.

Single doses of zoledronic acid should not exceed 5 mg and the duration of the intravenous infusion should be no less than 15 minutes.

5. Pharmacological Properties

5.1 Mechanism of Action

Zoledronic acid belongs to the bisphosphonate class and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.

5.2 Pharmacodynamic Properties

The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid rapidly partitions to bone and, as with other bisphosphonates, localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate (FPP) synthase. The relatively long duration of action of zoledronic acid is attributable to its strong binding affinity to bone mineral.

In the reference osteoporosis treatment trial, the effect of zoledronic acid treatment on markers of bone resorption (serum beta-C-telopeptides ) and bone formation (bone-specific alkaline phosphatase , serum N-terminal propeptide of type I collagen ) was evaluated in patients (subsets ranging from 517 to 1,246 patients) at periodic intervals. Treatment with a 5 mg annual dose of zoledronic acid reduces bone turnover markers to the premenopausal range, with an approximate 55% reduction in b-CTx, a 29% reduction in BSAP, and a 52% reduction in P1NP over 36 months. There was no progressive reduction of bone turnover markers with repeated annual dosing.

In a reference clinical study which was conducted in paediatric patients aged 5 to 17 years treated with glucocorticoids who had decreased bone mineral density (lumbar spine BMD Z-score of -0.5 or less) and a low impact/fragility fracture. Zoledronic acid infusion resulted in an increase in the lumbar spine BMD Z-score least square (LS) mean difference of 0.41 at month 12 relative to baseline and statistically significant (p<0.05) reduction in three bone turnover markers (P1NP, BSAP, NTX) was observed compared to placebo (95% CI: 0.02, 0.81; 18 and 16 patients, respectively). No new vertebral fractures were observed in the zoledronic acid group as compared to two new fractures in the placebo group. The most commonly reported adverse reactions after infusion of zoledronic acid were arthralgia (28%), pyrexia (22%), vomiting (22%), headache (22%), nausea (17%), myalgia (17%), pain (17%), diarrhoea (11%) and hypocalcaemia (11%). More patients reported serious adverse events in the zoledronic acid group than in the placebo group (5 patients versus 1 patient). In the 12-month open-label extension of the above-mentioned core study, no new clinical fractures were observed. However, 2 patients, one in each of the core study treatment groups (zoledronic acid group: 1/9, 11.1% and placebo group: 1/14, 7.1%), had new morphometric vertebral fractures. There were no new safety findings.  Long-term safety data in this population cannot be established from this study.

5.3 Pharmacokinetic Properties

Pharmacokinetic data in patients with osteoporosis and Paget's disease of bone are not available.

Distribution

Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg zoledronic acid were given to 64 patients with cancer and bone metastases. The post-infusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process showing a rapid decrease from peak concentrations at end-of-infusion to <1% of the Cmax 24 hours post-infusion, with population half-lives of t1/2(alpha) at 0.24 hours and t1/2(beta) at 1.87 hours for the early disposition phases of the drug. The terminal elimination phase of zoledronic acid was prolonged, with very low concentrations in plasma between days 2 and 28 post-infusion, and a terminal elimination half-life t1/2(gamma) of 146 hours. The area under the plasma concentration versus time curve (AUC0–24h) of zoledronic acid was dose-proportional from 2–16 mg. The accumulation of zoledronic acid measured over three cycles was low, with mean AUC0–24h ratios for cycles 2 and 3 versus 1 of 1.13 ± 0.30 and 1.16 ± 0.36, respectively.

In vitro and ex vivo reference studies showed low affinity of zoledronic acid for the cellular components of human blood. In vitro mean zoledronic acid protein-binding in human plasma ranged from 28% at 200 ng/mL to 53% at 50 ng/mL.

Metabolism

Zoledronic acid does not inhibit human cytochrome (CY) P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In reference animal studies, <3% of the administered intravenous dose was found in the faeces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidneys. Following an intravenous dose of 20 nCi 14C-zoledronic acid in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of the parent drug was recovered in urine, which suggests that zoledronic acid is not metabolized.

Excretion

In 64 patients with cancer and bone metastases, on average (± S.D.), 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-day 2. The cumulative percent of drug excreted in the urine over 0–24 hours was independent of dose. The balance of drug not recovered in urine over 0–24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0–24 hour renal clearance of zoledronic acid was 3.7 ± 2.0 L/h.

Zoledronic acid clearance was independent of dose but dependent upon the patient's creatinine clearance. In a reference study in patients with cancer and bone metastases, increasing the infusion time of a 4 mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion ( 403 ± 118 ng/mL versus 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng × h/mL versus 420 ± 218 ng × h/mL). The difference between the AUC means was not statistically significant.

Special Populations

Paediatric

Zoledronic acid is not indicated for use in children and adolescents below 18 years of age. There are no data available for children under 5 years of age.

Geriatric

The pharmacokinetics of zoledronic acid was not affected by age in patients with cancer and bone metastases whose age ranged from 38 years to 84 years.

Race

The pharmacokinetics of zoledronic acid was not affected by race in patients with cancer and bone metastases.

Hepatic Impairment

No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid.

Renal Impairment

The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately impaired renal function. Compared to patients with creatinine clearance >80 mL/min (N=37), patients with creatinine clearance = 50 to 80 mL/min (N=15) showed an average increase in plasma AUC of 15%, whereas patients with creatinine clearance = 30 to 50 mL/min (N=11) showed an average increase in plasma AUC of 43%. No dosage adjustment is required in patients with a creatinine clearance of greater than or equal to 35 mL/min. Zoledronic acid injection is contraindicated in patients with creatinine clearance <35 mL/min and in those with evidence of acute renal impairment due to an increased risk of renal failure.

6. Nonclinical Properties

6.1 Animal Toxicology or Pharmacology

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 reference 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 reference 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 and Developmental 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 in reference carcinogenicity studies.

Bone Safety Studies

Zoledronic acid is a potent inhibitor of osteoclastic bone resorption. In the ovariectomized rat, single IV doses of zoledronic acid of 4-500 mcg/kg (0.1 to 3.5 times the human 5 mg intravenous dose, based on body surface area mg/m2) suppressed bone turnover and protected against trabecular bone loss, cortical thinning and the reduction in vertebral and femoral bone strength in a dose-dependent manner. At a dose equivalent to human exposure at the 5 mg intravenous dose, the effect persisted for 8 months, which corresponds to approximately 8 remodeling cycles or 3 years in humans.

In ovariectomized rats and monkeys, weekly treatment with zoledronic acid dose-dependently suppressed bone turnover and prevented the decrease in cancellous and cortical BMD and bone strength, at yearly cumulative doses up to 3.5 times the intravenous human dose of 5 mg, based on a mg/m2 comparison. Bone tissue was normal and there was no evidence of a mineralization defect, no accumulation of osteoid, and no woven bone.

7. Description

ROKFOS contains zoledronic acid, which is a bisphosphonate that inhibits osteoclast-mediated bone resorption.

Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula.

8. Pharmaceutical Particulars

8.1 Incompatibility

Zoledronic acid must not be allowed to come into contact with any calcium-containing solutions.

Zoledronic acid must not be mixed or given intravenously with any other medicinal products.

8.2 Shelf-life

24 months.

8.3 Packaging Information

ROKFOS is available in a bottle of 100 ml.

8.4 Storage and Handling Instructions

  • Store the vial in its original carton at temperature 15-25°C, excursions permitted up to 30°C.
  • Keep out of the reach of children.
  • Do not mix with any calcium-containing solutions.

9.  Patient Counselling Information

  1. What ROKFOS is and what it is used for

ROKFOS contains the active substance zoledronic acid. It belongs to a group of medicines called bisphosphonates and is used to treat post-menopausal women and adult men with osteoporosis or osteoporosis caused by treatment with corticosteroids used to treat inflammation, and Paget’s disease of the bone in adults.

Osteoporosis

Osteoporosis is a disease that involves the thinning and weakening of the bones and is common in women after the menopause, but can also occur in men. At the menopause, a woman’s ovaries stop producing the female hormone oestrogen, which helps keep bones healthy. Following the menopause bone loss occurs, bones become weaker and break more easily. Osteoporosis could also occur in men and women because of the long-term use of steroids, which can affect the strength of bones. Many patients with osteoporosis have no symptoms but they are still at risk of breaking bones because osteoporosis has made their bones weaker. Decreased circulating levels of sex hormones, mainly oestrogens converted from androgens, also play a role in the more gradual bone loss observed in men. In both women and men, ROKFOS strengthens the bone and therefore makes it less likely to break. ROKFOS is also used in patients who have recently broken their hip in a minor trauma such as a fall and therefore are at risk of subsequent bone breaks.

Paget’s disease of the bone

It is normal that old bone is removed and is replaced with new bone material. This process is called remodelling. In Paget’s disease, bone remodelling is too rapid and new bone is formed in a disordered fashion, which makes it weaker than normal. If the disease is not treated, bones may become deformed and painful, and may break. ROKFOS works by returning the bone remodelling process to normal, securing formation of normal bone, thus restoring strength to the bone.

  1. What you need to know before you are given zoledronic acid

Follow all instructions given to you by your doctor, pharmacist or nurse carefully before you are given zoledronic acid.

You must not be given zoledronic acid:

  • if you are allergic to zoledronic acid, other bisphosphonates or any of the other ingredients of this medicine.
  • if you have hypocalcaemia (this means that the levels of calcium in your blood are too low).
  • if you have severe kidney problems.
  • if you are pregnant.
  • if you are breast-feeding.

Warnings and precautions

Talk to your doctor before you are given zoledronic acid:

  • if you are being treated with any medicine containing zoledronic acid, (zoledronic acid is used in adult patients with certain types of cancer to prevent bone complications or to reduce the amount of calcium).
  • if you have a kidney problem, or used to have one.
  • if you are unable to take daily calcium supplements or have low blood calcium levels.
  • if you have had some or all of the parathyroid glands in your neck surgically removed.
  • if you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome) or you have had sections of your intestine removed.
  • if you have asthma (wheezing) from taking aspirin

A side effect called osteonecrosis of the jaw (ONJ) (bone damage in the jaw) has been reported in the post-marketing setting in patients receiving zoledronic acid for osteoporosis. ONJ can also occur after stopping treatment.

It is important to try and prevent ONJ developing as it is a painful condition that can be difficult to treat. In order to reduce the risk of developing osteonecrosis of the jaw, there are some precautions you should take.

Before receiving zoledronic acid treatment, tell your doctor, pharmacist or nurse if

  • you have any problems with your mouth or teeth such as poor dental health, gum disease, or a planned tooth extraction;
  • you do not receive routine dental care or have not had a dental check-up for a long time;
  • you are a smoker (as this may increase the risk of dental problems);
  • you have previously been treated with a bisphosphonate (used to treat or prevent bone disorders);
  • you are taking medicines called corticosteroids (such as prednisolone or dexamethasone)
  • you have cancer.

Your doctor may ask you to undergo a dental examination before you start treatment with zoledronic acid.

While being treated with zoledronic acid, you should maintain good oral hygiene (including regular teeth brushing) and receive routine dental check-ups. If you wear dentures you should make sure these fit properly. If you are under dental treatment or are due to undergo dental surgery (e.g. tooth extractions), inform your doctor about your dental treatment and tell your dentist that you are being treated with zoledronic acid. Contact your doctor and dentist immediately if you experience any problems with your mouth or teeth such as loose teeth, pain or swelling, or non-healing of sores or discharge, as these could be signs of osteonecrosis of the jaw.

Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture may include new or unusual pain in your hip, groin, or thigh.

Monitoring test

Your doctor should do a blood test to check your kidney function (levels of creatinine) before each dose of zoledronic acid. It is important for you to drink at least 2 glasses of fluid (such as water), within a few hours before receiving zoledronic acid, as directed by your healthcare provider.

Children and adolescents

zoledronic acid is not recommended for anyone under 18 years of age.

Other medicines and zoledronic acid

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

It is important for your doctor to know all the medicines you are taking, especially if you are taking any medicines known to be harmful to your kidneys (e.g. aminoglycosides), diuretics (“waterpills”) that may cause dehydration or Non-steroidal anti-inflammatory medicines (NSAIDS).

Pregnancy and breast-feeding

You must not be given zoledronic acid if you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby.

Ask your doctor, pharmacist or nurse for advice before taking this medicine.

Driving and using machines

If you feel dizzy while taking zoledronic acid, do not drive or use machines until you feel better.

  1. How zoledronic acid is given

Follow carefully all instructions given to you by your doctor or nurse. Check with your doctor or nurse if you are not sure. Before you receive Reclast, drink at least 2 glasses of fluid (such as water) within a few hours as directed by your doctor.

Osteoporosis

The usual dose is 5 mg given as one infusion per year into a vein by your doctor or nurse. The infusion will take at least 15 minutes.

In case you recently broke your hip, it is recommended that zoledronic acid is administered two or more weeks after your hip repair surgery.

It is important to take calcium and vitamin D supplements (for example tablets) as directed by your doctor.

For osteoporosis, zoledronic acid works for one year. Your doctor will let you know when to return for your next dose.

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 usual dose is 5 mg, given to you as one initial infusion into a vein by your doctor or nurse. The infusion will take at least 15 minutes. zoledronic acid may work for longer than one year, and your doctor will let you know if you need to be treated again.

Your doctor may advise you to take calcium and vitamin D supplements (e.g. tablets) for at least the first ten days after being given zoledronic acid. It is important that you follow this advice carefully so that the level of calcium in your blood does not become too low in the period after the infusion. Your doctor will inform you regarding the symptoms associated with hypocalcaemia.

Zoledronic acid with food and drink

Make sure you drink enough fluids (at least one or two glasses) before and after the treatment with zoledronic acid, as directed by your doctor. This will help to prevent dehydration. You may eat normally on the day you are treated with zoledronic acid. This is especially important in patients who take diuretics (“water pills”) and in elderly patients (age 65 years or over).

If you missed a dose of zoledronic acid

Contact your doctor or hospital as soon as possible to re-schedule your appointment.

Before stopping zoledronic acid therapy

If you are considering stopping zoledronic acid treatment, please go to your next appointment and discuss this with your doctor. Your doctor will advise you and decide how long you should be treated with zoledronic acid.

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

  1. Possible side effects

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

Side effects related to the first infusion are very common (occurring in more than 30% of patients) but are less common following subsequent infusions. The majority of the side effects, such as fever and chills, pain in the muscles or joints, and headache, occur within the first three days following the dose of zoledronic acid. The symptoms are usually mild to moderate and go away within three days. Your doctor can recommend a mild pain reliever such as ibuprofen or paracetamol to reduce these side effects. The chance of experiencing these side effects decreases with subsequent doses of zoledronic acid.

Some side effects could be serious

Common (may affect up to 1 in 10 people)

Irregular heart rhythm (atrial fibrillation) has been seen in patients receiving zoledronic acid for the treatment of postmenopausal osteoporosis. It is currently unclear whether zoledronic acid causes this irregular heart rhythm but you should report it to your doctor if you experience such symptoms after you have received zoledronic acid.

Uncommon (may affect up to 1 in 100 people)

Swelling, redness, pain and itching to the eyes or eye sensitivity to light.

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

Talk to your doctor if you have ear pain, discharge from the ear, and/or an ear infection. These could be signs of bone damage in the ear.

Not known (frequency cannot be estimated from the available data)

Pain in the mouth and/or jaw, swelling or non-healing sores in the mouth or jaw, discharge, numbness or a feeling of heaviness in the jaw, or loosening of a tooth; these could be signs of bone damage in the jaw (osteonecrosis). Tell your doctor and dentist immediately if you experience such symptoms while being treated with zoledronic acid or after stopping treatment.

Kidney disorders (e.g. decreased urine output) may occur. Your doctor should do a blood test to check your kidney function before each dose of zoledronic acid. It is important for you to drink at least 2 glasses of fluid (such as water), within a few hours before receiving zoledronic acid, as directed by your healthcare provider.

If you experience any of the above side effects, you should contact your doctor immediately.

Zoledronic acid may also cause other side effects

Very common (may affect more than 1 in 10 people)

Fever

Common (may affect up to 1 in 10 people)

Headache, dizziness, sickness, nausea, vomiting, diarrhoea, pain in the muscles, pain in the bones and/or joints, pain in the back, arms or legs, flu-like symptoms (e.g. tiredness, chills, joint and muscle pain), chills, feeling of tiredness and lack of interest, weakness, pain, feeling unwell, swelling and/or pain at the infusion site.

In patients with Paget’s disease, symptoms due to low blood calcium, such as muscle spasms, or numbness, or a tingling sensation especially in the area around the mouth have been reported.

Uncommon (may affect up to 1 in 100 people)

Flu, upper respiratory tract infections, decreased red cell count, loss of appetite, sleeplessness, sleepiness which may include reduced alertness and awareness, tingling sensation or numbness, extreme tiredness, trembling, temporary loss of consciousness, eye infection or irritation or inflammation with pain and redness, spinning sensation, increased blood pressure, flushing, cough, shortness of breath, upset stomach, abdominal pain, constipation, dry mouth, heartburn, skin rash, excessive sweating, itching, skin reddening, neck pain, stiffness in muscles, bones and/or joints, joint swelling, muscle spasms, shoulder pain, pain in your chest muscles and rib cage, joint inflammation, muscular weakness, abnormal kidney test results, abnormal frequent urination, swelling of hands, ankles or feet, thirst, toothache, taste disturbances.

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

Unusual fracture of the thigh bone particularly in patients on long-term treatment for osteoporosis may occur rarely. Contact your doctor if you experience pain, weakness or discomfort in your thigh, hip or groin as this may be an early indication of a possible fracture of the thigh bone. Low levels of phosphate in the blood.

Not known (frequency cannot be estimated from the available data)

Severe allergic reactions including dizziness and difficulty breathing, swelling mainly of the face and throat, decreased blood pressure, dehydration secondary to acute phase reaction (post-dose symptoms such as fever, vomiting and diarrhoea).

Reporting of side effects

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 18002677779 (Cipla Number) or you can report to PvPI on 1800 180 3024. By reporting side-effects, you can help provide more information on the safety of this product.

  1. How to store zoledronic acid

Your doctor, pharmacist or nurse knows how to store zoledronic acid properly.

  • Store the vial in its original carton at temperature 15-25°C, excursions permitted up to 30°C.
  • Keep this medicine out of the sight and reach of children.
  • Do not use this medicine after the expiry date which is stated on the carton and bottle after EXP.
  • After opening the bottle, the product should be used immediately in order to avoid microbial contamination. 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. Allow the refrigerated solution to reach room temperature before administration.

10. Details of Manufacturer

Natco Pharma Ltd.

Vijayapuri north, Nagarjunasagar – 508 202

Nalgonda district, Telangana, India

Registered Office:

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg

Lower Parel

Mumbai – 400 013, India

11. Details of Permission or Licence Number with Date

33/NG/AP/96/F-LVP/R granted on 23/09/1998

12. Date of Revision

 29/07/2020