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 osteoporosis therapy and represents an impor- tant step towards an improvement in the adherence to treatment.

In the hierarchy of diseases, much of the attention has been consumed by AIDS, polio, tuberculosis, hyperten- sion or diabetes.

But, at each medical conference, we receive more information about the cascading nature of osteoporotic fractures. A study presented some really disturbing data - once a woman suffers her first vertebral fracture, there is a five-fold increase in the chances that she will suffer a second fracture within a year.

It is, therefore, essential to prevent that first fracture because osteoporosis causes a huge amount of human suffering and it doesn't have to be that way.

Osteoporotic fractures represent a significant public health burden that is set to rise in future generations. Life expectancy is increasing around the globe, and the number of elderly individuals is rising within every geographic region. The world population is expected to rise from the current 323 million individuals aged 65 years to 1,555 million by the year 2050; in Asia exclusively, the number will grow from 145 million to 894 million.

These demographic changes alone can be expected to increase the number of hip fractures occurring among people aged 35 years worldwide. From 1.66 million in 1990, it is estimated to rise to 6.26 million in 2050, with most of the world's future hip fractures happening in Asia.

Compliance and persistence are crucial to achieve the optimal therapeutic results demonstrated in clinical trials in the patient's daily life situation.

Despite the availability of effective treatment for osteoporosis, poor adherence to drug regimens reduces the benefits and presents a major challenge. Most instances of inadequate compliance and persistence are seen within 3 months of the start of treatment. ⁵

In a longitudinal cohort study, only about 33% of patients on daily regimens and 45% on weekly regimens for osteoporosis achieved adequate adherence, defined as having taken more than 80% of their prescribed medication. ⁶

About 68% of patients on daily regimens and 56% of those on weekly regimens had discontinued treatment by 12 months from initiation. Other studies have shown similar trends. In a study of a large, geographically diverse, managed care plan, adherence to therapy among patients treated with alendronate (n=6,881) or risedronate (n=2,224) was evaluated. Persistence, defined as continuous therapy on the same drug for each month over the study period, was comparable between weekly and daily users; both exhibited drop offs within the first 3 months, followed by a steady decline through month 12. ⁶

In one study particularly, it was seen that the 1-year persistence rate with bisphosphonates was just 24%. ⁷

Poor adherence with treatments for osteoporosis has many adverse consequences. First, the therapeutic effect of the medications is diminished or absent. Second, the risk of adverse effects is increased if the medications are not taken as directed. Finally, poor adherence results in increased costs to society related both to the cost of the inadequately treated disease and to the cost of the incorrectly used medications.

Inadequate compliance and persistence are associated with higher rates of fracture than those observed when compliance and persistence are good.

In over 35,000 women on bisphosphonates, fracture rates in those who did not comply or persist with the treatment were 20-30% higher than those persisting with the medication, as prescribed, at 24 months. ^5,8

Injection ROKFOS contains Zoledronic Acid, which is a bisphosphonate that inhibits osteoclast-mediated bone resorption. The parent compound from which Zoledronic Acid is prepared is Zoledronic Acid monohydrate, which is designated chemically as (1-hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is as below:

Injection ROKFOS is available as a sterile solution (in COP* bottles) for intravenous infusion.

* Cyclic Olefin Polymer

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

The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intrave- nously administered Zoledronic Acid rapidly partitions to bone and, just like other bisphosphonates, localizes preferentially at the sites of high bone turnover. The main molecular target of Zoledronic Acid in the osteoclast is the synthase of the enzyme, farnesyl pyrophosphate (FPP) synthase. By inhibiting this enzyme, Zoledronic Acid accelerates the apoptosis of osteoclasts, but this does not exclude other inhibitory mechanisms. Therel tively long duration of action of Zoledronic Acid is attributable to its strong binding affinity to bone mineral.

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

Single or multiple 5-minute or 15-minute infusions of 2 mg, 4 mg, 8 mg 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 that showed a rapid decrease from peak concentrations at the end of the infusion to <1% of the C _max 24 hours post-infusion, with the population half-lives of t _1/2(alpha) being 0.24 hours and t _1/2(beta) being 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 with the terminal elimination half-life of t _1/2(gamma) at 146 hours. The area under the plasma concentration versus time curve (AUC _0-24h) of Zoledronic Acid was dose-proportional from 2 mg to 16 mg. The accumulation of Zoledronic Acid measured over three cycles was low, with the mean AUC _0-24h ratios for cycles 2 and 3, versus cycle 1, being 1.13 ± 0.30 and 1.16 ± 0.36, respectively.

In vitro and ex vivo studies showed a low affinity of Zoledronic Acid for the cellular components of human blood. Binding to human plasma proteins was approximately 22% and was independent of the concentration of Zoledronic Acid.

Zoledronic Acid does not inhibit the human cytochrome CYP450 enzymes in vitro. Zoledronic Acid does not undergo biotransformation in vivo. In 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 the urine, which suggests that Zoledronic Acid is not metabolized

In 64 patients with cancer and bone metastases, an average (mean ± S.D.) of 39 ± 16% of the administered Zoledronic Acid dose was recovered in the urine within 24 hours, with only trace amounts of drug being found in the 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 the 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 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 concentrtion at the end of the infusion ([mean ± S.D.] 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.

The Health Outcomes and Reduced Incidence with Zoledronic Acid Once-Yearly Pivotal Fracture Trial (HORIZON-T), which was conducted on 7,765 patients, demonstrated a significant reduction in the incidence of new vertebral fractures at 1, 2 and 3 years with Zoledronic Acid, as shown in Fig. 2.

At 3 years, Zoledronic Acid significantly reduced the relative risk of morphometric vertebral fracture by 70%.

Over a median duration of follow-up of 3 years, Zoledronic Acid significantly reduced the relative risk of hip fracture by 41% versus placebo (1.4% versus 2.5%; p=0.002).

Zoledronic Acid demonstrated superiority to placebo in reducing the incidence of all clinical fractures and clinical (symptomatic) vertebral and non-vertebral fractures, with a relative risk reduction of 25% for non-vertebral fractures, 33% for any clinical fracture and 77% for clinical vertebral fractures.

The HORIZON Recurrent Fracture Trial, involving patients with recent hip fracture, demonstrated that compared with placebo, the Zoledronic Acid group had a significantly reduced risk of clinical fractures by 35%, clinical vertebral fractures by 46%, non-vertebral fractures by 27% and hip fractures by 30%.

Bone biopsy specimens were obtained between months 33 and 36 from 82 postmenopausal patients with osteoporosis treated with three annual doses of Zoledronic Acid.

Qualitative, quantitative and micro CT assessments showed bone of normal architecture and quality without mineralization defects.

In a 3-year osteoporosis study, standing height was measured annually using a stadiometer.

The Zoledronic Acid group revealed less height loss compared to placebo (4.2 mm versus 7.0 mm, respectively [p<0.001]).

Patients on Zoledronic Acid had a 28% lower mortality risk compared with those receiving placebo infusions- the first time such a benefit has been reported for an osteoporosis medication.

Patients must be appropriately hydrated prior to the administration of Zoledronic Acid. This is especially important for the elderly and for patients receiving diuretic therapy. Zoledronic Acid can be dosed without regard to meals.

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 Zoledronic Acid administration. All patients should be instructed about the importance of calcium and vitamin D supplementation in maintaining serum calcium levels, and also about the symptoms of hypocalcaemia.

The incidence of post-dose symptoms occurring within the first 3 days after Zoledronic Acid infusion can be reduced by administering paracetamol or ibuprofen shortly following Zoledronic Acid administration.

Zoledronic Acid solution for infusion must not be allowed to come in contact with any calcium-containing solutions, and should be administered as a single intravenous solution through a separate vented infusion line.

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only OR for Specialist Use only
Zoledronic Acid (Injection)
Solution for Intravenous Infusion

Each 100 ml contains
Zoledronic Acid monohydrate equivalent to
Zoledronic Acid anhydrous....................5mg

Solution for infusion
Clear and colourless solution

ROKFOS contains Zoledronic Acid which is a bisphosphonate that inhibits osteoclast-mediated bone resorption

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

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

Single or multiple 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 Cmax 24 hours post infusion with population half-lives of t1/2(alpha) 0.24 hours and t1/2(beta) 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 to 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 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.

Zoledronic Acid does not inhibit human P450 enzymes in vitro. Zoledronic Acid does not undergo biotransformation in vivo. In animal studies, <3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney. 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 parent drug was recovered in urine, which suggests that Zoledronic Acid is not metabolized

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 presum- ably 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 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 ([mean ± SD] 403 ± 118 ng/mL vs 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng - h/mL vs. 420 ± 218 ng - h/mL). The difference between the AUC means was not statistically significant.

A single dose of ROKFOS Injection should not exceed 5 mg and the duration of infusion should be no less than 15 minutes.

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. Disturbances of calcium and mineral metabolism (e.g., hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine) must be effectively treated and clinical monitoring of calcium and mineral levels is highly recommended for these patients.

To reduce the risk of hypocalcaemia, all patients should receive 1500 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

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. 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, corticosteroids, poor oral hygiene).
While on treatment, these patients should avoid invasive dental procedures if possible. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. The clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates, including Zoledronic Acid.

Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with Zoledronic Acid have not been performed.

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.

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. 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 impact 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 a femur fracture. Subjects presenting with an atypical 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.

Caution is advised when bisphosphonates 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. Caution should also be exercised when Zoledronic Acid is used in combination with loop diuretics due to an increased risk of hypocalcaemia. Caution is indicated when Zoledronic Acid is used with other potentially nephrotoxic drugs.

No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of Zoledronic Acid. Zoledronic Acid does not inhibit human P450 enzymes in vitro, shows no biotransformation, and in animal studies <3 % of the administered dose was recovered in the feces.
This suggests no relevant role of liver function in the pharmacokinetics of Zoledronic Acid and no required dosage adjustment.

Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) 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 vs. oral) on this risk has not been established.

It is not known whether Zoledronic acid is excreted in human milk. Because many drugs are excreted in human milk, and because Zoledronic Acid binds to bone long-term, Zoledronic acid should not be administered to a lactating woman.

The safety and effectiveness of Zoledronic acid in pediatric patients have not been established.

Phase 3 studies of Zoledronic Acid in the treatment of Paget's disease of bone included 132 Zoledronic Acid -treated patients who were at least 65 years of age, while 68 Zoledronic Acid -treated patients were at least 75 years old. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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 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.

Local reactions at the infusion site such as redness, swelling and/or pain has been observed infrequently following the administration of Zoledronic Acid.

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

Osteonecrosis of the jaw has been reported with Zoledronic Acid.

Nausea, diarrhoea, constipation, dyspepsia, abdominal distension, abdominal pain and vomiting.

Treatment with intravenous bisphosphonates has been associated with renal dysfunction manifested as deterioration in renal function (i.e., increased serum creatinine) and in rare cases, acute renal failure. Renal dysfunction has been observed following the administration of Zoledronic Acid, especially in patients with pre-existing renal compromise or additional risk factors (e.g., oncology patients with chemotherapy, concomitant nephrotoxic medications, severe dehydration, etc), the majority of whom received a 4-mg dose every 3-4 weeks, but it has been observed in patients after a single administration. In clinical trials in Paget's disease there is no evidence of renal deterioration following a single 5-mg 15-minute infusion.

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

There is no experience of acute overdose with Zoledronic Acid Injection. Patients who have received doses higher than those recom- mended should be carefully monitored. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. 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 sulfate, respectively.
Single doses of ROKFOS should not exceed 5 mg and the duration of the intravenous infusion should be no less than 15 minutes.

2 years