Re-treatment of Paget’s Disease: After treatment with Aclasta in Paget’s disease an extended remission period is observed. At present, specific treatment data are not available. However, re-treatment with Aclasta may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, in patients who failed to achieve normalization of serum alkaline phosphatase, or in patients with symptoms, as dictated by medical practice 12 months after the initial dose.

Aclasta (5 mg in 100 mL ready-to-infuse solution) is administered IV via a vented infusion line, given at a constant infusion rate. The infusion must not be <15 min.

Patients must be appropriately hydrated prior to administration of Aclasta. This is especially important for patients receiving diuretic therapy.

Adequate calcium and vitamin D intake is important in women with osteoporosis if dietary intake is inadequate (see Precautions).

Elevated bone turnover is a characteristic of Paget’s disease of bone. It is strongly advised that patients with Paget’s disease receive the recommended daily allowance of supplemental calcium and vitamin D and this should be ensured during the initial 10 days following Aclasta administration.

For information on the infusion of Aclasta (see Instructions for Use and Handling under Cautions for Usage).

Patients with Renal Impairment: The use of Aclasta in patients with creatinine clearance <30 mL/min is not recommended due to lack of adequate clinical experience in this population.

No dose adjustment is necessary in patients with creatinine clearance ≥30 mL/min.

Patients with Hepatic Impairment: No dose adjustment is required (see Pharmacokinetics under Actions).

Elderly (≥65 years): No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger subjects.

Children and Adolescents: Aclasta has not been tested in children and adolescents and therefore should not be used in these age groups.

Use in pregnancy & lactation: There are no data on the use of zoledronic acid in pregnant women. Studies in animals have shown reproductive toxicological effects (see Toxicology under Action). The potential risk for humans is unknown. Aclasta is contraindicated during pregnancy and in breastfeeding women.

Patients must be appropriately hydrated prior to administration of Aclasta. This is especially important for patients receiving diuretic therapy.

Preexisting hypocalcemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with Aclasta (see Contraindications). Other disturbances of mineral metabolism must also be effectively treated (eg, diminished parathyroid reserve; intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients.

Elevated bone turnover is characteristic of Paget’s disease of bone. It is strongly advised that patients with Paget’s disease receive the recommended daily allowance of supplemental calcium and vitamin D and this should be ensured during the initial 10 days following Aclasta administration. Patients should be informed about symptoms of hypocalcemia. Physicians should consider clinical monitoring for patients at risk.

Adequate calcium and vitamin D intake is important in women with osteoporosis if dietary intake is inadequate.

Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Aclasta.

Aclasta contains the same active ingredient found in Zometa (zoledronic acid), used for oncology indications, and a patient being treated with Zometa should not be treated with Aclasta.

Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw has been reported predominantly in cancer patients treated with bisphosphonates, including zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures eg, tooth extraction. Many had signs of local infection including osteomyelitis. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (eg, cancer, chemotherapy, corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures 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. The clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

Effects on the Ability to Drive or Operate Machinery: There are no data to suggest that Aclasta affects the ability to drive or use machines.

The incidence of post-dose symptoms occurring within the first 3 days after administration of Aclasta, can be reduced by approximately 50% with the administration of paracetamol or ibuprofen shortly following Aclasta administration.

Very common (≥1/10), common (≥1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/1000, <1/10,000) adverse reactions suspected (investigator assessment) to be associated with Aclasta are shown as follows: Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse drug reactions suspected* (at least 1%) to be associated with Aclasta in postmenopausal osteoporosis in HORIZON-PFT study:

Nervous System Disorders: Common: Headache, dizziness. Uncommon: Lethargyb, paresthesia, somnolence, tremor, syncope, dysgeusia.

Eye Disorders: Uncommon: Conjunctivitis, eye pain, uveitis. Rare: Episcleritis, iritis.

Ear and Labyrinth Disorders: Uncommon: Vertigo.

Respiratory, Thoracic and Mediastinal Disorders: Common: Dyspneaa.

Gastrointestinal Disorders: Common: Nausea, vomiting, diarrhea. Uncommon: Dyspepsiab, abdominal pain, dry mouth, esophagitis.

Skin and Subcutaneous Tissue Disorders: Uncommon: Rash.

Musculoskeletal Disorders: Common: Myalgia, arthralgia, bone pain, back pain, pain in extremity. Uncommon: Joint swelling.

Renal and Urinary Disorders: Uncommon: Increase blood creatinine.

General Disorders and Administration Site Conditions: Very common: Fever. Common: Hypocalcemiaa, flu-like symptomsc, chills, fatigue, asthenia, pain, malaise, rigorsa. Uncommon: Anorexia, peripheral edema, thirst.

*Incidence based on investigator assessment of causality and includes those events with a greater frequency than placebo.

Key deviations in the adverse events in the Paget’s disease clinical trials compared to the postmenopausal HORIZON-PFT trial are summarized as follows:

a Common in Paget’s disease only.

b Common in Paget’s disease.

c Very common in Paget’s disease.

In one 3-year trial in postmenopausal osteoporosis women (HORIZON-PFT), the overall incidence of atrial fibrillation was low, reported in 2.5% of patients (96 out of 3862) in the Aclasta group vs. 1.9% of patients (75 out of 3852) in the placebo group. The increased incidence observed in this trial has not been observed in other clinical trials with zoledronic acid.

Class Effects: Renal Dysfunction: Treatment with IV bisphosphonates, including zoledronic acid, has been associated with renal dysfunction manifested as deterioration in renal function (ie, 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 preexisting renal compromise or additional risk factors (eg, oncology patients with chemotherapy, concomitant nephrotoxic medications, severe dehydration), 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 the HORIZON-PFT trial, the change in creatinine clearance (measured annually prior to dosing), and the incidence of renal failure and impairment was comparable for both the Aclasta and placebo treatment groups over 3 years. There was a transient increase in serum creatinine observed within 10 days in 1.8% of Aclasta-treated patients versus 0.8% of placebo-treated patients.

Laboratory Findings: In the HORIZON-PFT trial, approximately 0.2% of patients had notable declines of serum calcium levels (<1.87 mmol/L) following Aclasta administration. No symptomatic cases of hypocalcemia were observed.

In the Paget’s disease trials, symptomatic hypocalcemia was observed in approximately 1% of patients, all of which resolved.

Local Reactions: Local reactions at the infusion site eg, redness, swelling and/or pain were reported (0.7%) following the administration of zoledronic acid.

Osteonecrosis of the Jaw: Cases of osteonecrosis (primarily of the jaw) have been reported predominantly in cancer patients treated with bisphosphonates, including zoledronic acid (uncommon). Many of these patients had signs of local infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (eg, anemia, coagulopathies, infection, preexisting dental disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see Precautions). In the HORIZON-PFT trial in 7736 patients, ONJ has been reported in 1 patient treated with Aclasta and 2 patients treated with placebo. All 3 cases resolved.

Pharmacodynamic Effects: Osteoporosis: Aclasta treatment rapidly reduced the rate of bone turnover from elevated postmenopausal levels with the nadir for resorption markers observed at 7 days, and for formation markers at 12 weeks. Thereafter, bone markers stabilized within the pre-menopausal range. There was no progressive reduction of bone turnover markers with repeated annual dosing.

In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting bone formation, mineralization or the mechanical properties of bone. Histomorphometric data from long-term rat and monkey experiments showed the typical response of bone to an anti-resorptive agent with a dose-dependent reduction in osteoclastic activity and activation frequency of new remodelling sites in both trabecular and Haversian bone. Continuing bone remodelling was observed in bone samples from all animals treated with clinically relevant doses of zoledronic acid. There was no evidence of a mineralizing defect, no aberrant accumulation of osteoid, and no woven bone in treated animals.

Paget’s Disease of Bone: Paget’s disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disorderly bone remodelling. Excessive osteoclastic bone resorption is followed by irregular osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged and weakened bone structure. Clinical manifestations of Paget’s disease range from no symptoms to severe morbidity due to bone pain, bone deformity, pathological fractures and neurological and other complications. Serum alkaline phosphatase, the most frequently used biochemical index of disease activity, provides an objective measure of disease severity and response to therapy.

In two 6-month randomized comparative, well-controlled clinical trials, in patients with Paget’s disease, Aclasta demonstrated a superior and more rapid response compared with risedronate. In addition, biochemical markers of bone formation and resorption demonstrated normalization of bone turnover in more Aclasta-treated patients compared to risedronate-treated patients (see previous text).

Clinical Efficacy for the Treatment of Postmenopausal Osteoporosis: The efficacy and safety of Aclasta was demonstrated in HORIZON-PFT, a randomized, double-blind, placebo-controlled, multinational study of 7736 women aged 65-89 years with either: A femoral neck BMD T- score less than or equal to -1.5 and at least 2 mild or 1 moderate existing vertebral fracture(s); or a femoral neck BMD T-score less than or equal to -2.5 with or without evidence of an existing vertebral fracture(s). Aclasta was administered once a year for 3 consecutive years, as a single 5 mg dose in 100 mL solution infused over at least 15 min for a total of 3 doses. The 2 primary efficacy variables were the incidence of morphometric vertebral fractures at 3 years, and the incidence of hip fractures over a median duration of 3 years. 7736 women were evaluated for the incidence of hip and all clinical fractures. Of these, 5661 women were evaluated annually for incidence of vertebral fractures. Women who were evaluated for the incidence of vertebral fractures did not receive concomitant osteoporosis therapy, which was allowed for women contributing to the hip and all clinical fracture evaluations. Concomitant osteoporosis therapy included: Calcitonin, raloxifene, tamoxifen, hormone replacement therapy, tibolone; but excluded other bisphosphonates. All women received 1000-1500 mg of elemental calcium plus 400-1200 iu of vitamin D supplements per day.

Effect on Vertebral Fracture: Aclasta significantly decreased the incidence of greater than or equal to 1 new vertebral fractures over 3 years and as early as the 1 year timepoint (see Table 1).

Aclasta significantly decreased the risk of greater than or equal to 1 new/worsening vertebral fractures at 1 year (58%), 2 years (68%) and 3 years (67%) (all p<0.0001). Aclasta significantly decreased the risk of at least 1 new moderate or severe vertebral fracture at 1 year (60%), 2 years (71%) and 3 years (70%) (all p<0.0001).

The reductions in vertebral fractures >3 years were consistent and significantly greater than placebo regardless of age, geographical region, race, baseline body mass index, number of baseline vertebral fractures, femoral neck BMD T-score or prior bisphosphonate use. Specifically for patients greater than or equal to 75 years, Aclasta patients had a 61% reduction in the risk of vertebral fractures compared to placebo patients (p<0.0001).

Effect on Hip Fracture: Aclasta demonstrated a 40% reduction in the risk of hip fractures over 3 years. The hip fracture event rate was 1.45% for Aclasta-treated patients compared to 2.5% for placebo-treated patients. The effect over time is displayed in Figure 1.

In women who did not take concomitant osteoporosis therapy, Aclasta demonstrated a 40% reduction (p=0.0089) in the risk of hip fractures over this time period. In women who were allowed to take concomitant osteoporosis therapy, Aclasta demonstrated a 42% reduction (p=0.1707) in the risk of hip fractures over this time period.

The reductions in hip fractures over 3 years were greater than placebo regardless of age, geographical region, race, baseline body mass index, number of baseline vertebral fractures, or femoral neck BMD T-score.

Effect on All Clinical Fractures: Aclasta demonstrated superiority to placebo in reducing the incidence of all clinical fractures, clinical vertebral and non-vertebral fractures. All clinical fractures were verified based on the radiographic and/or clinical evidence. A summary of results is presented in Table 2.

Effect on Bone Mineral Density (BMD): Aclasta significantly increased BMD at the lumbar spine, hip, and distal radius relative to treatment with placebo at all timepoints (6,12, 24 and 36 months). Treatment with Aclasta resulted in an 6.9% increase in BMD at the lumbar spine, 6% at the total hip, 5% at the femoral neck and 3.2% at the distal radius over 3 years as compared to placebo.

Bone Histology: Dynamic bone histomorphometry in 36 postmenopausal patients with osteoporosis treated with 3 annual doses of Aclasta showed bone of normal quality with no evidence of impaired bone remodelling and no evidence of mineralization defects. Microcomputed tomography analysis demonstrated preservation of trabecular bone architecture in patients treated with Aclasta compared to placebo.

Bone Turnover Markers: Bone specific alkaline phosphatase (BSAP), serum N-terminal propeptide of type I collagen (P1NP) and serum b-C-telopeptides (b-CTx) were evaluated in subsets ranging from 517-1246 patients at periodic intervals throughout the study. Treatment with a 5-mg annual dose of Aclasta reduces bone turnover markers to the pre-menopausal range. Repeat dosing does not lead to further reduction of bone turnover markers.

Effect on Height: In the 3-year osteoporosis study standing height was measured annually using a stadiometer. The Aclasta group revealed less height loss compared to placebo (4.2 mm vs. 6.7 mm, respectively (p<0.0001)).

Days of Disability: Aclasta significantly reduced both the days of limited activity and the days of bed rest due to back pain and due to fractures compared to placebo (all p<0.01).

Clinical Efficacy for the Treatment of Paget’s Disease of the Bone: Aclasta was studied in male and female patients aged >30 years with primary mild to moderate Paget’s disease of the bone (median serum alkaline phosphatase level 2.6-3 times the upper limit of the age-specific normal reference range at the time of study entry) confirmed by radiographic evidence.

The efficacy of 1 infusion of 5 mg zoledronic acid versus daily doses of 30 mg risedronate for 2 months was demonstrated in two 6-month comparative trials. Therapeutic response was defined as either normalization of serum alkaline phosphatase (SAP) or a reduction of at least 75% from baseline in total SAP excess at the end of 6 months. SAP excess was defined as the difference between the measured level and midpoint of the normal range.

In both trials, zoledronic acid demonstrated a superior and more rapid therapeutic response compared with risedronate as evidenced by biochemical markers of formation (SAP), serum N-terminal propeptide of type I collagen (P1NP) and resorption (serum CTx 1 (cross-linked C-telopeptides of type I collagen) and urine a-CTx).

In combined data from both trials, after 2 months, Aclasta showed a superior therapeutic response of 90% (158/176) and SAP normalization rate of 63% (111/176) compared to 47% (81/171) and 26% (45/171) respectively for risedronate (all p<0.001). After 6 months, Aclasta showed 96% (169/176) and 89% (156/176) response and normalization rates compared to 74% (127/171) and 58% (99/171) for risedronate (all p<0.001).

In the pooled results, a similar decrease in pain severity and pain interference scores relative to baseline were observed over 6 months for Aclasta and risedronate.

The therapeutic response by subgroup is presented in Table 3.

Patients who were classified as responders at the end of the 6-month core study were eligible to enter an extended follow-up period. Of the 143 Aclasta-treated patients and 107 risedronate-treated patients who entered an extended observation study, after a median duration of follow-up of 18 months from time of dosing, 141 Aclasta-treated patients maintained their therapeutic response compared to 71 risedronate-treated patients.

The cumulative rate of maintaining therapeutic response in the extended follow-up period is displayed in Figure 2.

*Time to first loss of therapeutic response: The occurrence of an SAP level that no longer meets the criteria of a therapeutic response (<75% reduction in SAP excess and/or SAP above the upper limit of the normal range).

Bone histology was evaluated in 7 patients with Paget’s disease 6 months after treatment with 5 mg zoledronic acid. Bone biopsy results showed bone of normal quality with no evidence of impaired bone remodelling and no evidence of mineralization defects. These results were consistent with biochemical marker evidence of normalization of bone turnover.

Bone Safety Studies: Dose-response and duration of action of a single IV injection of zoledronic acid (0.8-500 mcg/kg) were investigated in ovariectomized adult rats for 8 months after dosing, which corresponds to approximately 8 remodelling cycles over 2.7 years in humans. A single dose of zoledronic acid protected against ovariectomy-induced bone loss; both the magnitude and duration of the effect were dose-dependent. The 2 highest doses of 100 and 500 mcg/kg significantly increased total bone mineral density, trabecular bone volume, trabecular number and connectivity density to levels above those of the sham-operated controls. Lower doses produced a weaker and less prolonged effect. Mechanical testing at study termination showed a dose-dependent increase in bone strength to values above those of the sham-operated controls at the higher dose. Histomorphometric analysis and measurement of plasma osteocalcin levels confirmed that bone formation was present at 32 weeks post-injection even at the highest dose of 500 mcg/kg. This dose in rats is approximately 3.4-fold higher than the 5-mg dose administered to a 50-kg patient. Similar results showing a dose-dependent improvement in bone mass and strength were obtained when weekly SC injections of zoledronic acid were given to ovariectomized rats (0.3-7.5 mcg/kg for 52 weeks) and ovariectomized monkeys (0.5-12.5 mcg/kg for 69 weeks). Overall, the results provide preclinical evidence for the efficacy and bone safety of zoledronic acid at clinically relevant doses.

In addition, 2 studies were performed in ovariectomized (OVX) rats (12-month treatment with 0.3, 1.5 and 7.5 mcg/kg) and OVX rhesus monkeys (16-month treatment with 0.5, 2.5 and 12.5 mcg/kg) using once-a-week SC injections. Zoledronic acid treatment dose-dependently prevented all the OVX-induced changes in bone mineral density, bone mechanics and biochemical markers of bone metabolism in serum and urine. Often, full efficacy was achieved with the intermediate dose, whereas the low dose had either no or only a slight effect. Drug treatment was well tolerated and there were no clinically meaningful adverse events in either species. Static and dynamic histomorphometric analysis of bones from both of these experiments indicated that zoledronic acid dose-dependently prevented the changes induced by OVX in both trabecular and Haversian bone. Moreover, there was no indication of any abnormality in bone or marrow tissue, no evidence of a mineralizing defect, no accumulation of osteoid, and no woven bone. Except for its high antiresorptive potency, the effect of zoledronic acid on bone was qualitatively similar to that published for other bisphosphonates. These results demonstrate bone safety in a laboratory rodent and a non-human primate species with a more frequent dosing regimen and a 5- to 8-fold higher total yearly dose (based on 5-mg human dose), than the planned once-a-year dosing in humans.

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

After initiation of the zoledronic acid infusion, plasma concentrations of the active substance increased rapidly, achieving their peak at the end of the infusion period, followed by a rapid decline to <10% of peak after 4 hrs and <1% of peak after 24 hrs, with a subsequent prolonged period of very low concentrations not exceeding 0.1% of peak levels.

IV administered zoledronic acid is eliminated by a triphasic process: Rapid biphasic disappearance from the systemic circulation, with half-lives of t½a 0.24 and t½b 1.87 hrs, followed by a long elimination phase with a terminal elimination half-life of t½g 146 hrs. There was no accumulation of the active substance in plasma after multiple doses given every 28 days. The early disposition phases (a and b, with t½ values mentioned previously) presumably represent rapid uptake into bone and excretion via the kidneys.

Zoledronic acid is not metabolized and is excreted unchanged via the kidney. Over the first 24 hrs, 39䔴% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. From the bone tissue it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04± 2.5 L/hr, independent of dose and unaffected by gender, age, race or body weight. The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively. Increasing the infusion time from 5-15 min caused a 30% decrease in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.

No specific drug-drug interaction studies have been conducted with zoledronic acid. Since zoledronic acid is not metabolized in humans and the substance was found to have little or no capacity as a direct-acting and/or irreversible metabolism-dependent inhibitor of P-450 enzymes, zoledronic acid is unlikely to reduce the metabolic clearance of substances which are metabolized via the cytochrome P-450 enzyme systems. Zoledronic acid is not highly bound to plasma proteins (approximately 43-55% bound) and binding is concentration-independent. Therefore, interactions resulting from displacement of highly protein-bound drugs are unlikely.

Special Populations (see Dosage & Administration): The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 75䕅% of the creatinine clearance, which showed a mean of 84䕁 mL/min (range 22-143 mL/min) in the 64 patients studied. Small observed increases in AUC(0-24hr), by about 30-40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (ClCr=50-80 mL/min) and moderate (ClCr=30-50 mL/min) renal impairment are not necessary. As only limited data are available in severe renal impairment (creatinine clearance <30 mL/min), no dosing recommendations are possible for this population.

Toxicology: Preclinical Safety Data: Acute Toxicity: The highest non-lethal single IV dose was 10 mg/kg body weight in mice and 0.6 mg/kg in rats. In the single-dose dog infusion studies, 1 mg/kg (6-fold the recommended human therapeutic exposure based on AUC) administered over 15 min was well tolerated with no renal effects.

Subchronic and Chronic Toxicity: In the bolus parenteral studies, zoledronic acid was well tolerated when administered SC to rats and IV to dogs at doses of up to 0.02 mg/kg daily for 4 weeks. Administration of 0.001 mg/kg/day SC in rats and 0.005 mg/kg IV once every 2-3 days in dogs for up to 52 weeks was also well tolerated. In IV infusion studies, renal tolerability occurred in rats at doses of up to 0.6 mg/kg given as 6 infusions at 3-day intervals (6-fold the clinical dose), while 5 infusions of 0.25 mg/kg administered at 2- to 3-week intervals (7-fold the clinical dose) were well tolerated in dogs.

Longer-term repeat administration at cumulative exposures sufficiently exceeding the maximum intended human exposure produced toxicological effects in other organs, including the GIT and liver, and at the site of IV administration. The clinical relevance of these findings is unknown. The most frequent finding in the repeat-dose studies consisted of increased primary spongiosa in the metaphyses of long bones in growing animals at nearly all doses, a finding that reflected the compound’s pharmacological antiresorptive activity.

Reproduction Toxicity: Teratology studies were performed in 2 species, both via SC administration. Teratogenicity was observed in the rat at doses greater than or equal to 0.2 mg/kg and was manifested by external, visceral and skeletal malformations. No teratological or embryo/fetal effects were observed in the rabbit, 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.