Zoledronic Acid

Zoledronic acid is a third-generation, nitrogen-containing bisphosphonate. It acts mainly on bone, where it inhibits osteoclastic bone resorption; in long-term animal studies it did so without adversely affecting bone formation, mineralisation or mechanical properties. The same active substance is used at two doses: 4 mg in patients with cancer involving bone (Zometa) and 5 mg in osteoporosis and Paget’s disease of the bone (Aclasta).

Mechanism of Action

• Targeting of bone: bisphosphonates have a high affinity for mineralised bone and bind to hydroxyapatite. Bone resorption by osteoclasts acidifies the bone surface and releases the bound drug, which the osteoclast then takes up.
• Osteoclast inhibition: nitrogen-containing bisphosphonates inhibit enzymes of the mevalonate pathway, including farnesyl diphosphate synthase. This prevents the prenylation of GTP-binding proteins such as Rap1, interferes with their function and can lead to apoptosis. The Zometa SmPC states that the precise molecular mechanism of the inhibition of osteoclast activity is still unclear.
• Anti-tumour properties (preclinical): in animals, less bone resorption alters the bone marrow microenvironment so that it is less favourable to tumour growth, and anti-angiogenic and anti-pain activity were seen. In vitro, zoledronic acid inhibited osteoblast proliferation, had direct cytostatic and pro-apoptotic effects on tumour cells, acted synergistically with other anti-cancer drugs and reduced tumour cell adhesion and invasion.
• Clinical effect in cancer: in the first randomised, double-blind, placebo-controlled study (prostate cancer), 4 mg reduced the proportion of patients with at least one skeletal-related event (SRE), delayed the median time to the first SRE by more than 5 months and lowered the skeletal morbidity rate. Multiple-event analysis showed a 36% reduction in the risk of SREs compared with placebo.

Pharmacokinetics

The figures below are from the Zometa SmPC (64 patients with bone metastases given 2, 4, 8 or 16 mg as 5- or 15-minute infusions; the parameters were independent of dose).

• Absorption and distribution: given intravenously. Plasma concentrations peak at the end of the infusion, fall to below 10% of the peak after 4 hours and below 1% after 24 hours, and then stay very low (not above 0.1% of the peak before the next dose 28 days later). Zoledronic acid shows no appreciable binding to plasma proteins in vitro; the part of the dose not excreted in the urine is principally bound to bone tissue.
• Metabolism: not metabolised (no biotransformation), and it does not inhibit human cytochrome P450 enzymes in vitro.
• Elimination: triphasic. After a rapid two-phase decline (half-lives 0.24 and 1.87 hours) there is a long terminal half-life of 146 hours. In the first 24 hours 39 ± 16% of the dose is excreted unchanged in the urine; the bone-bound remainder is released very slowly and also leaves through the kidney. Total body clearance is 5.04 ± 2.5 L/h, independent of dose and unaffected by sex, age, race and body weight. There was no accumulation with doses every 28 days. Lengthening the infusion from 5 to 15 minutes lowered the end-of-infusion concentration by 30% but did not change the area under the curve.
• Special populations: renal clearance follows creatinine clearance (about 75 ± 33% of it; mean creatinine clearance 84 ± 29 mL/min, range 22 to 143, in the 64 patients), and reduced doses are used in mild to moderate renal impairment (see Administration and Dosage). There are no pharmacokinetic data in hypercalcaemia or hepatic insufficiency; animal data (below 3% of the dose in faeces) suggest that liver function plays no relevant part. Variability between patients is high.

Zometa (4 mg) is indicated in adults for:

• Advanced malignancies involving bone: prevention of skeletal-related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia).
• Tumour-induced hypercalcaemia (TIH): treatment.

The SmPCs for the powder and solvent and for the concentrate give these two indications. The Zometa product information also holds a separate SmPC for the 4 mg/100 mL solution for infusion.

Aclasta (5 mg) is indicated for:

• Osteoporosis: treatment in post-menopausal women and in adult men at increased risk of fracture, including those with a recent low-trauma hip fracture.
• Osteoporosis associated with long-term systemic glucocorticoid therapy: treatment in post-menopausal women and in adult men at increased risk of fracture.
• Paget’s disease of the bone: treatment in adults.

• Zometa: hypersensitivity to zoledronic acid, to other bisphosphonates or to any of the excipients; breast-feeding.
• Aclasta: hypersensitivity to zoledronic acid, to any bisphosphonate or to any of the excipients; hypocalcaemia; severe renal impairment with creatinine clearance below 35 mL/min; pregnancy and breast-feeding.

The Zometa and Aclasta SmPCs each have their own table of adverse reactions, summarised separately below.

Zometa (4 mg)

Within three days of a Zometa dose an acute phase reaction is commonly reported, with bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis with joint swelling; these symptoms usually resolve within a few days. The important identified risks are renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, atrial fibrillation, anaphylaxis and interstitial lung disease. The frequencies come from clinical studies and post-marketing reports, mainly after chronic treatment with 4 mg.

Very common (≥1/10): hypophosphataemia.

Common (≥1/100 to <1/10): anaemia, headache, conjunctivitis, nausea, vomiting, decreased appetite, bone pain, myalgia, arthralgia, generalised pain, renal impairment, fever, flu-like syndrome (including fatigue, rigors, malaise and flushing), increased blood creatinine and blood urea, hypocalcaemia.

Uncommon (≥1/1,000 to <1/100): thrombocytopenia, leukopenia, hypersensitivity reaction, anxiety, sleep disturbance, dizziness, paraesthesia, dysgeusia, hypoaesthesia, hyperaesthesia, tremor, somnolence, blurred vision, scleritis and orbital inflammation, hypertension, hypotension, atrial fibrillation, hypotension leading to syncope or circulatory collapse, dyspnoea, cough, bronchoconstriction, diarrhoea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth, pruritus, rash (including erythematous and macular rash), increased sweating, muscle spasms, osteonecrosis of the jaw, acute renal failure, haematuria, proteinuria, asthenia, peripheral oedema, injection site reactions (pain, irritation, swelling, induration), chest pain, weight increase, anaphylactic reaction or shock, urticaria, hypomagnesaemia, hypokalaemia.

Rare (≥1/10,000 to <1/1,000): pancytopenia, angioneurotic oedema, confusion, uveitis, bradycardia, cardiac arrhythmia (secondary to hypocalcaemia), interstitial lung disease, acquired Fanconi syndrome, arthritis and joint swelling as a symptom of the acute phase reaction, hyperkalaemia, hypernatraemia.

Very rare (<1/10,000): convulsions, hypoaesthesia and tetany (secondary to hypocalcaemia), episcleritis, osteonecrosis of the external auditory canal (a bisphosphonate class reaction) and of other sites including the femur and hip.

Not known: tubulointerstitial nephritis.

Aclasta (5 mg)

Adverse reactions occurred in 44.7%, 16.7% and 10.2% of patients after the first, second and third infusion. After the first infusion the most frequent were pyrexia (17.1%), myalgia (7.8%), influenza-like illness (6.7%), headache (5.1%) and arthralgia (4.8%), which are the acute phase reactions described under Special Instructions.

Very common (≥1/10): pyrexia.

Common (≥1/100 to <1/10): hypocalcaemia (common in Paget’s disease only), headache, dizziness, ocular hyperaemia, atrial fibrillation, nausea, vomiting, diarrhoea, myalgia, arthralgia, bone pain, back pain, pain in extremity, influenza-like illness, chills, fatigue, asthenia, pain, malaise, infusion site reaction, increased C-reactive protein.

Uncommon (≥1/1,000 to <1/100): influenza, nasopharyngitis, anaemia, decreased appetite, insomnia, lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia, conjunctivitis, eye pain, vertigo, palpitations, hypertension, flushing, cough, dyspnoea, dyspepsia, upper abdominal pain, abdominal pain, gastro-oesophageal reflux disease, constipation, dry mouth, oesophagitis, toothache, gastritis (observed in patients also taking glucocorticosteroids), rash, hyperhidrosis, pruritus, erythema, neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness, increased blood creatinine, pollakiuria, proteinuria, peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain, decreased blood calcium.

Rare (≥1/10,000 to <1/1,000): hypophosphataemia, uveitis, episcleritis, iritis, atypical subtrochanteric and diaphyseal femoral fractures (a bisphosphonate class reaction identified after marketing).

Very rare (<1/10,000): osteonecrosis of the external auditory canal (a bisphosphonate class reaction).

Not known (post-marketing reports; frequency cannot be estimated): hypersensitivity reactions including rare cases of bronchospasm, urticaria and angioedema and very rare cases of anaphylactic reaction or shock; scleritis and parophthalmia; hypotension (some of the patients had underlying risk factors); osteonecrosis of the jaw; renal impairment, with rare cases of renal failure needing dialysis and rare fatal cases in patients with existing renal dysfunction or other risk factors; dehydration secondary to acute phase reactions.

Selected reactions described in the Aclasta SmPC:

• Acute phase reactions (post-menopausal osteoporosis study): fever 18.1%, myalgia 9.4%, flu-like symptoms 7.8%, arthralgia 6.8% and headache 6.5%, mostly in the first 3 days, mostly mild to moderate and settling within 3 days; they were less frequent with later annual doses.
• Atrial fibrillation: in the pivotal fracture trial 2.5% (96 of 3,862) with Aclasta and 1.9% (75 of 3,852) with placebo; serious atrial fibrillation 1.3% against 0.6%. The mechanism is unknown, and across the pooled osteoporosis trials the rates were comparable (2.6% against 2.1%).
• Hypocalcaemia: in osteoporosis trials about 0.2% of patients had a notable fall in serum calcium (below 1.87 mmol/L), none with symptoms; in Paget’s disease trials symptomatic hypocalcaemia occurred in about 1%, all resolving. It was much less frequent after later infusions.
• Osteonecrosis of the jaw: in a trial of 7,736 patients it was reported in one Aclasta-treated and one placebo-treated patient; further cases have been reported after marketing.

Zometa: in clinical studies it was given with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions. No formal clinical interaction studies have been done. Zoledronic acid shows no appreciable binding to plasma proteins and does not inhibit human cytochrome P450 enzymes in vitro.

• Aminoglycosides, calcitonin and loop diuretics: these may add to the effect of bisphosphonates, lowering serum calcium for longer than required. Use with caution.
• Other medicines that cause hypocalcaemia: may have a synergistic effect and lead to severe hypocalcaemia.
• Other potentially nephrotoxic medicines: use with caution, and watch for hypomagnesaemia.
• Thalidomide: in multiple myeloma, the risk of renal dysfunction may be higher when Zometa is combined with thalidomide.
• Anti-angiogenic medicines: caution, as more osteonecrosis of the jaw has been seen when they are given together.
• Other bisphosphonates and Aclasta: patients on Zometa should not receive Aclasta or any other bisphosphonate at the same time.

Aclasta: use with caution with other medicines that can affect renal function; concomitant diuretic therapy is a risk factor for renal impairment. Patients on Aclasta should not be given other zoledronic acid products used in oncology, or any other bisphosphonate. Section 4.5 of the Aclasta SmPC gives the full text.

Zometa must be prescribed and given only by healthcare professionals experienced in giving intravenous bisphosphonates, and patients should receive the package leaflet and the patient reminder card. Aclasta for Paget’s disease should be prescribed only by physicians experienced in treating Paget’s disease of the bone. All presentations are given as an intravenous infusion. Patients must be well hydrated before the infusion, and with Zometa also afterwards.

Zometa: Skeletal-Related Events and Hypercalcaemia

• Prevention of skeletal-related events (adults and older people): 4 mg every 3 to 4 weeks, with an oral calcium supplement of 500 mg and 400 IU of vitamin D daily. The effect of treatment starts after 2–3 months, which should be considered when deciding whether to treat bone metastases.
• Tumour-induced hypercalcaemia (adults and older people): a single 4 mg dose when the albumin-corrected serum calcium is 12.0 mg/dL (3.0 mmol/L) or higher.
• Method: the powder and solvent, once reconstituted, and the concentrate are each further diluted in 100 mL (see section 6.6 of the SmPC) and given as a single intravenous infusion over no less than 15 minutes. Zometa must not be mixed with calcium or other divalent cation-containing infusion solutions such as lactated Ringer’s solution, and is given as a single intravenous solution in a separate infusion line. The separate SmPC for the 4 mg/100 mL solution gives the preparation of that presentation.

Zometa: Renal Impairment and Children

• Tumour-induced hypercalcaemia: in severe renal impairment, treatment should be considered only after weighing risks and benefits. Patients with serum creatinine above 400 µmol/L (4.5 mg/dL) were excluded from the trials; no adjustment is needed with serum creatinine below that level.
• Skeletal-related events: serum creatinine and creatinine clearance (Cockcroft-Gault) are measured before starting. Treatment is not recommended with severe renal impairment (creatinine clearance below 30 mL/min); trials excluded serum creatinine above 265 µmol/L (3.0 mg/dL). For mild to moderate impairment (creatinine clearance 30–60 mL/min) the recommended dose is: above 60 mL/min, 4.0 mg; 50–60 mL/min, 3.5 mg; 40–49 mL/min, 3.3 mg; 30–39 mL/min, 3.0 mg. These doses aim at the exposure seen at a creatinine clearance of 75 mL/min.
• Reduced doses: withdraw 4.4 mL for 3.5 mg, 4.1 mL for 3.3 mg or 3.8 mL for 3.0 mg, from the reconstituted solution (4 mg/5 mL) of the powder or from the concentrate. Dilute the withdrawn volume in 100 mL of sterile 0.9% sodium chloride or 5% glucose solution and give over no less than 15 minutes.
• Monitoring: serum creatinine is measured before each dose, and treatment is withheld if renal function has worsened (in trials, a rise of 0.5 mg/dL or 44 µmol/L from a normal baseline creatinine, or of 1.0 mg/dL or 88 µmol/L from an abnormal baseline). It was resumed only when creatinine was back within 10% of baseline, at the same dose as before the interruption.
• Children: safety and efficacy in children aged 1 to 17 years have not been established, and no dose recommendation can be made.

Aclasta: Osteoporosis and Paget’s Disease

• Preparation of the patient: appropriate hydration before the infusion, especially in people aged 65 years or more and those taking diuretics. Adequate calcium and vitamin D intake is recommended.
• Osteoporosis (post-menopausal women, men, and glucocorticoid-associated osteoporosis): a single intravenous infusion of 5 mg once a year. The best duration of treatment has not been established; the need to continue should be reviewed regularly on the benefits and risks for the individual, particularly after 5 or more years.
• Recent low-trauma hip fracture: give the infusion at least two weeks after repair of the fracture; a loading dose of 50,000 to 125,000 IU of vitamin D, by mouth or intramuscular injection, is recommended before the first infusion.
• Paget’s disease: a single intravenous infusion of 5 mg, with at least 500 mg of elemental calcium twice daily for at least 10 days afterwards. In patients who relapse, re-treatment is a further 5 mg infusion after an interval of one year or longer; data on re-treatment are limited.
• Infusion: a single dose must not exceed 5 mg and the infusion must last at least 15 minutes.
• Renal impairment: contraindicated if creatinine clearance is below 35 mL/min; no adjustment at 35 mL/min or above. Hepatic impairment: no adjustment is required. The Aclasta SmPC gives the details for older people and for children.

Same Active Substance in Both Products

Zometa and Aclasta contain the same active substance. A patient treated with one should not be given the other, or any other bisphosphonate, at the same time, because the combined effects are unknown.

Hydration and Metabolic Monitoring

Patients must be adequately hydrated before each infusion. With Zometa, overhydration should be avoided in patients at risk of cardiac failure, and serum calcium, phosphate and magnesium are carefully monitored after treatment starts; short-term supplements may be needed for hypocalcaemia, hypophosphataemia or hypomagnesaemia. Patients with untreated hypercalcaemia generally have some renal impairment, so careful monitoring of renal function should be considered.

Renal Impairment

• Zometa: renal dysfunction has been reported. Risk factors are dehydration, existing renal impairment, multiple cycles of Zometa or other bisphosphonates, and other nephrotoxic medicines. Renal deterioration, progression to renal failure and dialysis have been reported after the first or a single 4 mg dose, and serum creatinine can rise with chronic use. Creatinine is assessed before every dose, and treatment is withheld if renal function worsens. Use is not recommended in severe renal impairment.
• Aclasta: contraindicated if creatinine clearance is below 35 mL/min. Renal impairment has followed Aclasta, even after a single dose, especially with existing renal dysfunction or risks such as advanced age, nephrotoxic medicines, diuretic therapy or dehydration after the infusion; renal failure needing dialysis, or fatal, has occurred rarely. Creatinine clearance is calculated from actual body weight with the Cockcroft-Gault formula before each dose, and serum creatinine monitoring should be considered in patients at risk.

Hepatic Insufficiency

With Zometa, only limited clinical data are available in severe hepatic insufficiency, so no specific recommendation can be given. With Aclasta, no dose adjustment is required in hepatic impairment.

Hypocalcaemia

• Zometa: hypocalcaemia has been reported; cardiac arrhythmias and neurological events (convulsions, hypoaesthesia, tetany) have followed severe hypocalcaemia, sometimes needing hospital admission and in some cases life-threatening. Serum calcium must be measured and hypocalcaemia corrected before treatment starts, and patients should receive adequate calcium and vitamin D.
• Aclasta: existing hypocalcaemia must be treated with calcium and vitamin D before treatment, and other disturbances of mineral metabolism (for example reduced parathyroid reserve or intestinal calcium malabsorption) must also be treated. In Paget’s disease, bone turnover is high and transient, sometimes symptomatic, hypocalcaemia can develop, usually greatest within the first 10 days; serum calcium should be measured before the infusion and patients told about the symptoms.

Osteonecrosis of the Jaw and Other Sites

• Osteonecrosis of the jaw (ONJ) has been reported uncommonly in Zometa clinical trials, with more reports after marketing in advanced breast cancer and multiple myeloma, and after marketing with Aclasta in osteoporosis.
• Starting treatment, or a new course, should be delayed in patients with unhealed open soft tissue lesions in the mouth (for Zometa, except in medical emergencies). A dental examination with preventive dentistry and an individual benefit–risk assessment is recommended before treatment in patients with risk factors: a potent bisphosphonate given parenterally and cumulative dose; cancer, anaemia, coagulopathies, infection or smoking; chemotherapy, angiogenesis inhibitors, radiotherapy to the head and neck or corticosteroids; and poor oral hygiene, periodontal disease, poorly fitting dentures, a history of dental disease or invasive dental procedures such as tooth extraction.
• Patients should keep good oral hygiene, have routine dental check-ups and report any oral symptom at once (loose teeth, pain, swelling, sores that do not heal, discharge). Invasive dental procedures should be done only with careful consideration and be avoided close to an infusion; in ONJ, dental surgery may make the condition worse. If ONJ develops, a management plan is set up with a dentist or oral surgeon experienced in ONJ, and a temporary break in treatment should be considered.
• Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly after long-term therapy (risk factors include steroids, chemotherapy, local infection or trauma); consider it in patients with ear symptoms such as chronic ear infections. Osteonecrosis at other sites, including the hip and femur, has been reported sporadically, mainly in adult cancer patients treated with Zometa.

Atypical Femoral Fractures

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonates, mainly in people on long-term osteoporosis treatment. They occur after minimal or no trauma, may be preceded by thigh or groin pain for weeks to months, are often bilateral and may heal poorly. After a femoral shaft fracture the other femur should be examined. Patients should report thigh, hip or groin pain and be evaluated for an incomplete femoral fracture; stopping the bisphosphonate should be considered while a suspected fracture is evaluated.

Musculoskeletal Pain

Severe and occasionally incapacitating bone, joint or muscle pain has been reported infrequently with bisphosphonates, including Zometa and Aclasta. With Zometa it began from one day to several months after starting; most patients improved after stopping, and some had the pain again when treated again with Zometa or another bisphosphonate.

Acute Phase Reaction

Fever, myalgia, flu-like symptoms, arthralgia and headache may follow Aclasta, mostly within three days, and can sometimes be serious or prolonged. Paracetamol or ibuprofen shortly after the infusion can reduce them. It is advisable to postpone Aclasta if the patient is clinically unstable because of an acute medical condition and an acute phase reaction could be problematic.

Pregnancy, Breastfeeding and Fertility

• Zometa: there are no adequate data in pregnant women; animal studies show reproductive toxicity and the risk to humans is unknown. Zometa should not be used in pregnancy, and women who can become pregnant should be advised to avoid it. It is not known whether zoledronic acid passes into human milk; Zometa is contraindicated in breast-feeding. In rats, effects on fertility were masked by exaggerated pharmacological effects (periparturient hypocalcaemia, difficult birth, early end of the study), so an effect on human fertility could not be determined.
• Aclasta: not recommended in women of childbearing potential, and contraindicated in pregnancy and breast-feeding. There are no adequate data in pregnant women; animal studies showed reproductive toxicity, including malformations, and the risk to humans is unknown.

Sodium

Zometa contains less than 1 mmol (23 mg) of sodium per dose, so it is essentially sodium-free; if 0.9% sodium chloride is used for dilution, the sodium dose is higher. Aclasta contains less than 1 mmol (23 mg) of sodium per 100 mL bottle.

Effect on Driving

With Zometa, adverse reactions such as dizziness and somnolence may affect the ability to drive or use machines, so caution is needed.

Zometa powder and solvent, Zometa 4 mg/5 mL concentrate and Aclasta do not require any special storage conditions, so no cold chain is needed. The separate SmPC for Zometa 4 mg/100 mL solution gives the storage conditions of that presentation. For reconstituted, diluted and opened solutions, see Shelf Life.

• Zometa powder and solvent: 3 years. After reconstitution and dilution, the solution should be used immediately from a microbiological point of view; if not, in-use times and conditions are the user’s responsibility and would normally not be longer than 24 hours at 2–8 °C. The refrigerated solution is then brought to room temperature before it is given.
• Zometa 4 mg/5 mL concentrate: 3 years. After dilution, the same applies: use immediately, or normally no longer than 24 hours at 2–8 °C, then bring to room temperature before giving.
• Aclasta: 3 years for the unopened bottle. After opening, from a microbiological point of view the product should be used immediately; if not, in-use times and conditions are the user’s responsibility and would normally not be longer than 24 hours at 2–8 °C.
• Zometa 4 mg/100 mL solution: see its SmPC.

Prescription only (Rx). Zometa is prescribed and given by healthcare professionals experienced in intravenous bisphosphonates, and Aclasta for Paget’s disease by physicians experienced in treating that disease. Both are intravenous infusions given by healthcare professionals, so they are supplied to the hospital or clinic that administers them. No cold chain is needed.