Zoledronic acid-injection

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Before receiving zoledronic acid injection,

• tell your doctor and pharmacist if you are allergic to zoledronic acid or any other medications, or any of the ingredients in zoledronic acid injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
• you should know that zoledronic acid injection is available under the brand names Zometa and Reclast. You should only be treated with one of these products at a time.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: aminoglycoside antibiotics such as amikacin (Amikin), gentamicin (Garamycin), kanamycin (Kantrex), neomycin (Neo-Rx, Neo-Fradin), paromomycin (Humatin), streptomycin, and tobramycin (Tobi, Nebcin); aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin) and naproxen (Aleve, Naprosyn); cancer chemotherapy medications; digoxin (Lanoxin, in Digitek); diuretics ('water pills') such as bumetanide (Bumex), ethacrynic acid (Edecrin), and furosemide (Lasix); and oral steroids such as dexamethasone (Decadron, Dexone), methylprednisolone (Medrol), and prednisone (Deltasone). Many other medications may interact with zoledronic acid, so tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had kidney disease or if you have a dry mouth, dark urine, decreased sweating, dry skin, and other signs of dehydration or recently have had diarrhea, vomiting, fever, infection, excessive sweating, or have been unable to drink enough fluids. Your doctor will wait until you are no longer dehydrated before giving you zoledronic acid injection or if you have certain types of kidney disease may not prescribe this treatment for you. Also tell your doctor if you have ever had a low level of calcium in your blood. Your doctor will probably check the level of calcium in your blood before you begin treatment and may not prescribe this medication if the level is too low.
• tell your doctor if you have been treated with zoledronic acid or other bisphosphonates (Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa) in the past; if you have ever had surgery on your parathyroid gland (small gland in the neck) or thyroid gland or surgery to remove sections of your small intestine; and if you have or have ever had heart failure (condition in which the heart cannot pump enough blood to other parts of the body); anemia (condition in which red blood cells cannot bring enough oxygen to other parts of the body); any condition that stops your blood from clotting normally; low levels of calcium, magnesium, or potassium in your blood; any condition that prevents your body from absorbing nutrients from food; or problems with your mouth, teeth, or gums; an infection, especially in your mouth; asthma or wheezing, especially if it is made worse by taking aspirin; or parathyroid or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You should use a reliable method of birth control to prevent pregnancy while you are receiving zoledronic acid. If you become pregnant while receiving zoledronic acid, call your doctor. Zoledronic acid may harm the fetus. Talk to your doctor if you plan to become pregnant at any time in the future because zoledronic acid may remain in your body for years after you stop receiving it.
• you should know that zoledronic acid injection may cause severe bone, muscle, or joint pain. You may begin to feel this pain within daysor months after you first receive zoledronic acid injection. Although this type of pain may begin after you have received zoledronic acid injection for some time, it is important for you and your doctor to realize that it may be caused by zoledronic acid. Call your doctor right away if you experience severe pain at any time during your treatment with zoledronic acid injection. Your doctor may stop giving you zoledronic acid injection and your pain may go away after you stop treatment with this medication.
• you should know that zoledronic acid may cause osteonecrosis of the jaw (ONJ, a serious condition of the jaw bone), especially if you have dental surgery or treatment while you are using the medication. A dentist should examine your teeth and perform any needed treatments, including cleaning, before you start to use zoledronic acid. Be sure to brush your teeth and clean your mouth properly while you are using zoledronic acid. Talk to your doctor before having any dental treatments while you are using this medication.

Read the Patient Information Leaflet if available from your pharmacist before you start receiving zoledronic acid and each time you get a treatment. If you have any questions, ask your doctor or pharmacist.This medication is given by injection into a vein as directed by your doctor, usually over at least 15 minutes. The dosage is based on your medical condition (including your kidney function) and response to treatment.If you are giving this medication to yourself at home, learn all preparation and usage instructions from your health care professional. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.Avoid mixing zoledronic acid with IV fluids that have calcium in them (such as Ringer's solution, Hartmann's solution, parenteral nutrition-TPN/PPN). Talk to your pharmacist for more details.For the treatment of high blood calcium levels, fluids are usually given through a vein before you receive this medication. To decrease the chance of kidney problems, drink plenty of fluids during treatment unless otherwise directed by your doctor. It takes at least 7 days after a dose to get the full benefit of this drug. The dose may need to be repeated depending on your blood calcium levels.For the treatment of multiple myeloma and bone problems caused by the spread of cancer, this medication is usually given every 3 to 4 weeks or as directed by your doctor. You may also be instructed to take calcium and vitamin D supplements each day.

If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: change in the amount of urine, muscle spasms, muscle weakness, mental/mood changes, irregular heartbeat, seizures.

Reclast contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is:

Zoledronic acid monohydrate is a white crystalline powder. Its molecular formula is C5H10N2O7P2 • H2O and a molar mass of 290.1 g/Mol. Zoledronic acid monohydrate is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid, and practically insoluble in organic solvents. The pH of the Reclast solution for infusion is approximately 6.0 - 7.0.

Reclast Injection is available as a sterile solution in bottles for intravenous infusion. One bottle with 100 mL solution contains 5.330 mg of zoledronic acid monohydrate, equivalent to 5 mg zoledronic acid on an anhydrous basis.

Inactive Ingredients: 4950 mg of mannitol, USP; and 30 mg of sodium citrate, USP.

Reclast®
(RE-clast)
(zoledronic acid) Injection

Read the Medication Guide that comes with Reclast before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about Reclast.

What is the most important information I should know about Reclast?

You should not receive Reclast if you are already receiving Zometa. Both Reclast and Zometa contain zoledronic acid.

Reclast can cause serious side effects including:

1. Low calcium levels in your blood (hypocalcemia)
2. Severe kidney problems
3. Severe jaw bone problems (osteonecrosis)
4. Bone, joint or muscle pain
5. Unusual thigh bone fractures

1. Low calcium levels in your blood (hypocalcemia). Reclast may lower the calcium levels in your blood. If you have low blood calcium before you start taking Reclast, it may get worse during treatment. Your low blood calcium must be treated before you take Reclast. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:

• Spasms, twitches, or cramps in your muscles
• Numbness or tingling in your fingers, toes, or around your mouth

Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood, while you take Reclast. Take calcium and vitamin D as your doctor tells you to.

2. Severe kidney problems.

Severe kidney problems may happen when you take Reclast. Severe kidney problems may lead to hospitalization or kidney dialysis and can be life-threatening. Your risk of kidney problems is higher if you:

• already have kidney problems
• take a diuretic or “water pill”
• do not have enough water in your body (dehydrated) before or after you receive Reclast
• are of advanced age since the risk increases as you get older
• take any medicines known to harm your kidneys

You should drink at least 2 glasses of fluid within a few hours before receiving Reclast to reduce the risk of kidney problems.

3. Severe jaw bone problems (osteonecrosis).

Severe jaw bone problems may happen when you take Reclast. Your doctor should examine your mouth before you start Reclast. Your doctor may tell you to see your dentist before you start Reclast. It is important for you to practice good mouth care during treatment with Reclast.

4. Unusual thigh bone fractures.

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.

5. Possible harm to your unborn baby.

Reclast should not be used if you are pregnant. Tell your doctor right away if you are pregnant or plan to become pregnant. Reclast may harm your unborn baby.

6. Bone, joint, or muscle pain.

Some people who take bisphosphonates develop severe bone, joint, or muscle pain.

Call your doctor right away if you have any of these side effects.

What is Reclast?

Reclast is a prescription medicine used to:

• Treat or prevent osteoporosis in women after menopause. Reclast helps reduce the chance of having a hip or spinal fracture (break).
• Increase bone mass in men with osteoporosis.
• Treat or prevent osteoporosis in either men or women who will be taking corticosteroid medicines for at least one year.
• Treat certain men and women who have Paget's disease of the bone.

It is not known how long Reclast works for the treatment and prevention of osteoporosis. You should see your doctor regularly to determine if Reclast is still right for you.

Reclast is not for use in children.

Who should not take Reclast?

Do not take Reclast if you:

• Have low levels of calcium in your blood
• Have kidney problems
• Are allergic to zoledronic acid or any of its ingredients. A list of ingredients is at the end of this leaflet.

What should I tell my doctor before taking Reclast?

Before you start Reclast, be sure to talk to your doctor if you:

• Have low blood calcium.
• Have kidney problems.
• Had parathyroid or thyroid surgery (glands in your neck).
• Have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome) or have had parts of your intestine removed.
• Have asthma (wheezing) from taking aspirin.
• Plan to have dental surgery or teeth removed.
• Are pregnant, or plan to become pregnant. Reclast may harm your unborn baby. Reclast should not be used if you are pregnant.
• Are breastfeeding or plan to breastfeed. It is not known if Reclast passes into your milk and may harm your baby.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Certain medicines may affect how Reclast works.

Especially tell your doctor if you are taking:

• An antibiotic. Certain antibiotic medicines called aminoglycosides may increase the effect of Reclast in lowering your blood calcium for a long period of time.
• A diuretic or “water pill”.
• Non-steroidal anti-inflammatory medicines (NSAIDS).

Ask your doctor or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine.

How will I receive Reclast?

• Your doctor will tell you how often you will receive Reclast.
• Reclast is given by infusion into your vein (intravenously). Your infusion should last at least 15 minutes.
• Before you receive Reclast, drink at least 2 glasses of fluid (such as water) within a few hours as directed by your doctor.
• You may eat before your treatment with Reclast.
• If you miss a dose of Reclast, call your doctor or healthcare provider to schedule your next dose.

What are the possible side effects of Reclast?

Reclast may cause serious side effects.

• See “What is the most important information I should know about Reclast?”

The most common side effects of Reclast included:

• Fever
• Flu-like illness (fever, chills, bone, joint, or muscle pain, fatigue)
• Pain in your bones, joints or muscles
• Nausea
• Pain in your arms and legs
• Vomiting
• Headache
• Diarrhea

Talk to your doctor about things you can do to help decrease some of these side effects that might happen with a Reclast infusion.

You may get allergic reactions, such as hives, swelling of your face, lips, tongue, or throat.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Reclast. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about safe and effective use of Reclast.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. This Medication Guide summarizes the most important information about Reclast. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Reclast that is written for health professionals.

For more information, go to: www.pharma.us.novartis.com or call 1-888-669-6682.

What are the ingredients in Reclast?

Active ingredient: zoledronic acid monohydrate.

Inactive ingredients: mannitol and sodium citrate.

Your doctor or pharmacist can provide more information about zoledronic acid.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Treatment Of Osteoporosis In Postmenopausal Women

The safety of Reclast in the treatment of postmenopausal osteoporosis was assessed in Study 1, a large, randomized, double-blind, placebo-controlled, multinational study of 7736 postmenopausal women aged 65 to 89 years with osteoporosis, diagnosed by bone mineral density or the presence of a prevalent vertebral fracture. The duration of the trial was three years with 3862 patients exposed to Reclast and 3852 patients exposed to placebo administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes, for a total of three doses. All women received 1000 to 1500 mg of elemental calcium plus 400 to 1200 international units of vitamin D supplementation per day.

The incidence of all-cause mortality was similar between groups: 3.4% in the Reclast group and 2.9% in the placebo group. The incidence of serious adverse events was 29.2% in the Reclast group and 30.1% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.4% and 4.8% for the Reclast and placebo groups, respectively.

The safety of Reclast in the treatment of osteoporosis patients with a recent (within 90 days) low-trauma hip fracture was assessed in Study 2, a randomized, double-blind, placebo-controlled, multinational endpoint-driven study of 2127 men and women aged 50 to 95 years; 1065 patients were randomized to Reclast and 1062 patients were randomized to placebo. Reclast was administered once annually as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. The study continued until at least 211 patients had a confirmed clinical fracture in the study population who were followed for an average of approximately 2 years on study drug. Vitamin D levels were not routinely measured but a loading dose of vitamin D (50,000 to 125,000 international units orally or IM) was given to patients and they were started on 1000 to 1500 mg of elemental calcium plus 800 to 1200 international units of vitamin D supplementation per day for at least 14 days prior to the study drug infusions.

The incidence of all-cause mortality was 9.6% in the Reclast group and 13.3% in the placebo group. The incidence of serious adverse events was 38.3% in the Reclast group and 41.3% in the placebo group. The percentage of patients who withdrew from the study due to adverse events was 5.3% and 4.7% for the Reclast and placebo groups, respectively.

Adverse reactions reported in at least 2% of patients with osteoporosis and more frequently in the Reclast-treated patients than placebo-treated patients in either osteoporosis trial are shown below in Table 1.

Table 1: Adverse Reactions Occurring in greater than or equal to 2.0% of Patients with Osteoporosis and More Frequently than in Placebo-Treated Patients

System Organ Class	Study 1		Study 2
	5 mg IV Reclast once per year % (N=3862)	Placebo once per year % (N=3852)	5 mg IV Reclast once per year % (N=1054)	Placebo once per year % (N=1057)
Blood and the Lymphatic System Disorders
Anemia	4.4	3.6	5.3	5.2
Metabolism and Nutrition Disorders
Dehydration	0.6	0.6	2.5	2.3
Anorexia	2.0	1.1	1.0	1.0
Nervous System Disorders
Headache	12.4	8.1	3.9	2.5
Dizziness	7.6	6.7	2.0	4.0
Ear and Labyrinth Disorders
Vertigo	4.3	4.0	1.3	1.7
Cardiac Disorders
Atrial Fibrillation	2.4	1.9	2.8	2.6
Vascular Disorders
Hypertension	12.7	12.4	6.8	5.4
Gastrointestinal Disorders
Nausea	8.5	5.2	4.5	4.5
Diarrhea	6.0	5.6	5.2	4.7
Vomiting	4.6	3.2	3.4	3.4
Abdominal Pain Upper	4.6	3.1	0.9	1.5
Dyspepsia	4.3	4.0	1.7	1.6
Musculoskeletal, Connective Tissue and Bone Disorders
Arthralgia	23.8	20.4	17.9	18.3
Myalgia	11.7	3.7	4.9	2.7
Pain in Extremity	11.3	9.9	5.9	4.8
Shoulder Pain	6.9	5.6	0.0	0.0
Bone Pain	5.8	2.3	3.2	1.0
Neck Pain	4.4	3.8	1.4	1.1
Muscle Spasms	3.7	3.4	1.5	1.7
Osteoarthritis	9.1	9.7	5.7	4.5
Musculoskeletal Pain	0.4	0.3	3.1	1.2
General Disorders and Administrative Site Conditions
Pyrexia	17.9	4.6	8.7	3.1
Influenza-like Illness	8.8	2.7	0.8	0.4
Fatigue	5.4	3.5	2.1	1.2
Chills	5.4	1.0	1.5	0.5
Asthenia	5.3	2.9	3.2	3.0
Peripheral Edema	4.6	4.2	5.5	5.3
Pain	3.3	1.3	1.5	0.5
Malaise	2.0	1.0	1.1	0.5
Hyperthermia	0.3	< 0.1	2.3	0.3
Chest Pain	1.3	1.1	2.4	1.8
Investigations
Creatinine Renal Clearance Decreased	2.0	2.4	2.1	1.7

Renal Impairment

Treatment with intravenous bisphosphonates, including 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. In the clinical trial for postmenopausal osteoporosis, patients with baseline creatinine clearance less than 30 mL/min (based on actual body weight), urine dipstick greater than or equal to 2+ protein or increase in serum creatinine of greater than 0.5 mg/dL during the screening visits were excluded. The change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the Reclast and placebo treatment groups over 3 years, including patients with creatinine clearance between 30-60 mL/min at baseline. Overall, there was a transient increase in serum creatinine observed within 10 days of dosing in 1.8% of Reclast-treated patients versus 0.8% of placebo-treated patients which resolved without specific therapy [see WARNINGS AND PRECAUTIONS].

Acute Phase Reaction

The signs and symptoms of acute phase reaction occurred in Study 1 following Reclast infusion including fever (18%), myalgia (9%), flu-like symptoms (8%), headache (7%), and arthralgia (7%). The majority of these symptoms occurred within the first 3 days following the dose of Reclast and usually resolved within 3 days of onset but resolution could take up to 7-14 days. In Study 2, patients without a contraindication to acetaminophen were provided with a standard oral dose at the time of the IV infusion and instructed to use additional acetaminophen at home for the next 72 hours as needed. Reclast was associated with fewer signs and symptoms of a transient acute phase reaction in this trial: fever (7%) and arthralgia (3%). The incidence of these symptoms decreased with subsequent doses of Reclast.

Laboratory Findings

In Study 1, in women with postmenopausal osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 7.5 mg/dL) following Reclast administration. No symptomatic cases of hypocalcemia were observed. In Study 2, following pre-treatment with vitamin D, no patients had treatment emergent serum calcium levels below 7.5 mg/dL.

Injection Site Reactions

In the osteoporosis trials, local reactions at the infusion site such as itching, redness and/or pain have been reported in 0% to 0.7% of patients following the administration of Reclast and 0% to 0.5% of patients following administration of placebo.

Osteonecrosis Of The Jaw

In the postmenopausal osteoporosis trial, Study 1, in 7736 patients, after initiation of therapy, symptoms consistent with ONJ occurred in one patient treated with placebo and one patient treated with Reclast. Both cases resolved after appropriate treatment [see WARNINGS AND PRECAUTIONS]. No reports of osteonecrosis of the jaw were reported in either treatment group in Study 2.

Atrial Fibrillation

In the postmenopausal osteoporosis trial, Study 1, adjudicated serious adverse events of atrial fibrillation in the zoledronic acid treatment group occurred in 1.3% of patients (50 out of 3862) compared to 0.4% (17 out of 3852) in the placebo group. The overall incidence of all atrial fibrillation adverse events in the zoledronic acid treatment group was reported in 2.5% of patients (96 out of 3862) in the Reclast group vs. 1.9% of patients (75 out of 3852) in the placebo group. Over 90% of these events in both treatment groups occurred more than a month after the infusion. In an ECG sub-study, ECG measurements were performed on a subset of 559 patients before and 9 to 11 days after treatment. There was no difference in the incidence of atrial fibrillation between treatment groups suggesting these events were not related to the acute infusions. In Study 2, adjudicated serious adverse events of atrial fibrillation in the zoledronic acid treatment group occurred in 1.0% of patients (11 out of 1054) compared to 1.2% (13 out of 1057) in the placebo group demonstrating no difference between treatment groups.

Ocular Adverse Events

Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid. In the osteoporosis trials, 1 (less than 0.1%) to 9 (0.2%) patients treated with Reclast and 0 (0%) to 1 (less than 0.1%) patient treated with placebo developed iritis/uveitis/episcleritis.

Prevention Of Osteoporosis In Postmenopausal Women

The safety of Reclast in postmenopausal women with osteopenia (low bone mass) was assessed in a 2-year randomized, multi-center, double-blind, placebo-controlled study of 581 postmenopausal women aged greater than or equal to 45 years. Patients were randomized to one of three treatment groups: (1) Reclast given at randomization and Month 12 (n=198); (2) Reclast given at randomization and placebo at Month 12 (n=181); and (3) placebo given at randomization and Month 12 (n=202). Reclast was administered as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. All women received 500 to 1200 mg elemental calcium plus 400 to 800 international units vitamin D supplementation per day.

The incidence of serious adverse events was similar for subjects given (1) Reclast at randomization and at Month 12 (10.6%), (2) Reclast at randomization and placebo given at Month 12 (9.4%), and (3) placebo at randomization and at Month 12 (11.4%). The percentages of patients who withdrew from the study due to adverse events were 7.1%, 7.2%, and 3.0% in the two Reclast groups and placebo group, respectively. Adverse reactions reported in at least 2% of patients with osteopenia and more frequently in the Reclast-treated patients than placebo-treated patients are shown in Table 2.

Table 2: Adverse Reactions Occurring in greater than or equal to 2% of Patients with Osteopenia and More Frequently than in Placebo-Treated Patients

System Organ Class	5 mg IV Reclast Once Per Year% (n=198)	5 mg IV Reclast Once% (n=181)	Placebo once per year% (n=202)
Metabolism and nutrition disorders
Anorexia	2.0	0.6	0.0
Nervous system disorders
Headache	14.6	20.4	11.4
Dizziness	7.6	6.1	3.5
Hypoesthesia	5.6	2.2	2.0
Ear and labyrinth disorders
Vertigo	2.0	1.7	1.0
Vascular disorders
Hypertension	5.1	8.3	6.9
Gastrointestinal disorders
Nausea	17.7	11.6	7.9
Diarrhea	8.1	6.6	7.9
Vomiting	7.6	5.0	4.5
Dyspepsia	7.1	6.6	5.0
Abdominal pain*	8.6	6.6	7.9
Constipation	6.6	7.2	6.9
Abdominal discomfort	2.0	1.1	0.5
Abdominal distension	2.0	0.6	0.0
Skin and subcutaneous tissue disorders
Rash	3.0	2.2	2.5
Musculoskeletal and connective tissue disorders
Arthralgia	27.3	18.8	19.3
Myalgia	19.2	22.7	6.9
Back pain	18.2	16.6	11.9
Pain in extremity	11.1	16.0	9.9
Muscle spasms	5.6	2.8	5.0
Musculoskeletal pain**	8.1	7.2	7.9
Bone pain	5.1	3.3	1.0
Neck pain	5.1	6.6	5.0
Arthritis	4.0	2.2	1.5
Joint stiffness	3.5	1.1	2.0
Joint swelling	3.0	0.6	0.0
Flank pain	2.0	0.6	0.0
Pain in jaw	2.0	3.9	2.5
General disorders and administration site conditions
Pain	24.2	14.9	3.5
Pyrexia	21.7	21.0	4.5
Chills	18.2	18.2	3.0
Fatigue	14.6	9.9	4.0
Asthenia	6.1	2.8	1.0
Peripheral edema	5.6	3.9	3.5
Non-cardiac chest pain	3.5	7.7	3.0
Influenza-like illness	1.5	3.3	2.0
Malaise	1.0	2.2	0.5
* Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one ADR ** Combined musculoskeletal pain and musculoskeletal chest pain as one ADR

Ocular Adverse Events

Cases of iritis/uveitis/episcleritis/conjunctivitis have been reported in patients treated with bisphosphonates, including zoledronic acid. In the osteoporosis prevention trial, 4 (1.1%) patients treated with Reclast and 0 (0%) patients treated with placebo developed iritis/uveitis.

Acute Phase Reaction

In patients given Reclast at randomization and placebo at Month 12, Reclast was associated with signs and symptoms of an acute phase reaction: myalgia (20.4%), fever (19.3%), chills (18.2%), pain (13.8%), headache (13.3%), fatigue (8.3%), arthralgia (6.1%), pain in extremity (3.9%), influenza-like illness (3.3%), and back pain (1.7%), which occurred within the first 3 days following the dose of Reclast. The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days.

Osteoporosis In Men

The safety of Reclast in men with osteoporosis or osteoporosis secondary to hypogonadism was assessed in a two year randomized, multicenter, double-blind, active controlled group study of 302 men aged 25 to 86 years. One hundred fifty three (153) patients were exposed to Reclast administered once annually with a 5 mg dose in 100 mL infused over 15 minutes for up to a total of two doses, and 148 patients were exposed to a commercially-available oral weekly bisphosphonate (active control) for up to two years. All participants received 1000 mg of elemental calcium plus 800 to 1000 international units of vitamin D supplementation per day.

The incidence of all-cause mortality (one in each group) and serious adverse events were similar between the Reclast and active control treatment groups. The percentage of patients experiencing at least one adverse event was comparable between the Reclast and active control groups, with the exception of a higher incidence of post-dose symptoms in the Reclast group that occurred within 3 days after infusion. The overall safety and tolerability of Reclast was similar to the active control.

Adverse reactions reported in at least 2% of men with osteoporosis and more frequently in the Reclast-treated patients than the active control-treated patients and either (1) not reported in the postmenopausal osteoporosis treatment trial or (2) reported more frequently in the trial of osteoporosis in men are presented in Table 3. Therefore, Table 3 should be viewed in conjunction with Table 1.

Table 3: Adverse Reactions Occurring in greater than or equal to 2% of Men with Osteoporosis and More Frequently in the Reclast-Treated Patients than the Active Control-Treated Patients and either (1) Not Reported in the Postmenopausal Osteoporosis Treatment Trial or (2) Reported More Frequently in this Trial

System Organ Class	5 mg IV Reclast once per year % (N=153)	Active Control once weekly % (N=148)
Nervous System Disorders
Headache	15.0	6.1
Lethargy	3.3	1.4
Eye Disorders
Eye pain	2.0	0.0
Cardiac Disorders
Atrial fibrillation	3.3	2.0
Palpitations	2.6	0.0
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea	6.5	4.7
Abdominal pain*	7.9	4.1
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis	2.6	2.0
Musculoskeletal, Connective Tissue and BoneDisorders
Myalgia	19.6	6.8
Musculoskeletal pain**	12.4	10.8
Musculoskeletal stiffness	4.6	0.0
Renal and Urinary Disorders
Blood creatinine increased	2.0	0.7
General Disorders and Administrative Site Conditions
Fatigue	17.6	6.1
Pain	11.8	4.1
Chills	9.8	2.7
Influenza-like illness	9.2	2.0
Malaise	7.2	0.7
Acute phase reaction	3.9	0.0
Investigations
C-reactive protein increased	4.6	1.4
* Combined abdominal pain, abdominal pain upper, and abdominal pain lower as one ADR ** Combined musculoskeletal pain and musculoskeletal chest pain as one ADR

Renal Impairment

Creatinine clearance was measured annually prior to dosing and changes in long-term renal function over 24 months were comparable in the Reclast and active control groups [see WARNINGS AND PRECAUTIONS].

Acute Phase Reaction

Reclast was associated with signs and symptoms of an acute phase reaction: myalgia (17.1%), fever (15.7%), fatigue (12.4%), arthralgia (11.1%), pain (10.5%), chills (9.8%), headache (9.8%), influenza-like illness (8.5%), malaise (5.2%), and back pain (3.3%), which occurred within the first 3 days following the dose of Reclast. The majority of these symptoms were mild to moderate and resolved within 3 days of the event onset but resolution could take up to 7-14 days. The incidence of these symptoms decreased with subsequent doses of Reclast.

Atrial Fibrillation

The incidence of all atrial fibrillation adverse events in the Reclast treatment group was 3.3% (5 out of 153) compared to 2.0% (3 out of 148) in the active control group. However, there were no patients with adjudicated serious adverse events of atrial fibrillation in the Reclast treatment group.

Laboratory Findings

There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL.

Injection Site Reactions

There were 4 patients (2.6%) on Reclast vs. 2 patients (1.4%) on active control with local site reactions.

Osteonecrosis Of The Jaw

In this trial there were no cases of osteonecrosis of the jaw [see WARNINGS AND PRECAUTIONS].

Glucocorticoid-Induced Osteoporosis

The safety of Reclast in men and women in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in a randomized, multicenter, double-blind, active controlled, stratified study of 833 men and women aged 18 to 85 years treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent). Patients were stratified according to the duration of their pre-study corticosteroid therapy: less than or equal to 3 months prior to randomization (prevention subpopulation), and greater than 3 months prior to randomization (treatment subpopulation).

The duration of the trial was one year with 416 patients exposed to Reclast administered once as a single 5 mg dose in 100 mL infused over 15 minutes, and 417 patients exposed to a commercially-available oral daily bisphosphonate (active control) for one year. All participants received 1000 mg of elemental calcium plus 400 to 1000 international units of vitamin D supplementation per day.

The incidence of all-cause mortality was similar between treatment groups: 0.9% in the Reclast group and 0.7% in the active control group. The incidence of serious adverse events was similar between the Reclast treatment and prevention groups, 18.4% and 18.1%, respectively, and the active control treatment and prevention groups, 19.8% and 16.0%, respectively. The percentage of subjects who withdrew from the study due to adverse events was 2.2% in the Reclast group vs. 1.4% in the active control group. The overall safety and tolerability were similar between Reclast and active control groups with the exception of a higher incidence of post-dose symptoms in the Reclast group that occurred within 3 days after infusion. The overall safety and tolerability profile of Reclast in glucocorticoid-induced osteoporosis was similar to the adverse events reported in the Reclast postmenopausal osteoporosis clinical trial.

Adverse reactions reported in at least 2% of patients that were either not reported in the postmenopausal osteoporosis treatment trial or reported more frequently in the treatment and prevention of glucocorticoid-induced osteoporosis trial included the following: abdominal pain (Reclast 7.5%; active control 5.0%), and musculoskeletal pain (Reclast 3.1%; active control 1.7%). Other musculoskeletal events included back pain (Reclast 4.3%, active control 6.2%), bone pain (Reclast 3.1%, active control 2.2%), and pain in the extremity (Reclast 3.1%, active control 1.2%). In addition, the following adverse events occurred more frequently than in the postmenopausal osteoporosis trial: nausea (Reclast 9.6%; active control 8.4%), and dyspepsia (Reclast 5.5%; active control 4.3%).

Renal Impairment

Renal function measured prior to dosing and at the end of the 12 month study was comparable in the Reclast and active control groups [see WARNINGS AND PRECAUTIONS].

Acute Phase Reaction

Reclast was associated with signs and symptoms of a transient acute phase reaction that was similar to that seen in the Reclast postmenopausal osteoporosis clinical trial.

Atrial Fibrillation

The incidence of atrial fibrillation adverse events was 0.7% (3 of 416) in the Reclast group compared to no adverse events in the active control group. All subjects had a prior history of atrial fibrillation and no cases were adjudicated as serious adverse events. One patient had atrial flutter in the active control group.

Laboratory Findings

There were no patients who had treatment emergent serum calcium levels below 7.5 mg/dL.

Injection Site Reactions

There were no local reactions at the infusion site.

Osteonecrosis Of The Jaw

In this trial there were no cases of osteonecrosis of the jaw [see WARNINGS AND PRECAUTIONS].

Paget's Disease Of Bone

In the Paget's disease trials, two 6-month, double-blind, comparative, multinational studies of 349 men and women aged greater than 30 years with moderate to severe disease and with confirmed Paget's disease of bone, 177 patients were exposed to Reclast and 172 patients exposed to risedronate. Reclast was administered once as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. Risedronate was given as an oral daily dose of 30 mg for 2 months.

The incidence of serious adverse events was 5.1% in the Reclast group and 6.4% in the risedronate group. The percentage of patients who withdrew from the study due to adverse events was 1.7% and 1.2% for the Reclast and risedronate groups, respectively.

Adverse reactions occurring in at least 2% of the Paget's patients receiving Reclast (single 5 mg intravenous infusion) or risedronate (30 mg oral daily dose for 2 months) over a 6-month study period are listed by system organ class in Table 4.

Table 4: Adverse Reactions Reported in at Least 2% of Paget's Patients Receiving Reclast (Single 5 mg intravenous Infusion) or Risedronate (Oral 30 mg Daily for 2 Months) Over a 6-Month Follow-Up Period

System Organ Class	5 mg IV Reclast % (N = 177)	30 mg/day x 2 Months risedronate % (N = 172)
Infections and Infestations
Influenza	7	5
Metabolism and Nutrition Disorders
Hypocalcemia	3	1
Anorexia	2	2
Nervous System Disorders
Headache	11	10
Dizziness	9	4
Lethargy	5	1
Paresthesia	2	0
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea	5	1
Gastrointestinal Disorders
Nausea	9	6
Diarrhea	6	6
Constipation	6	5
Dyspepsia	5	4
Abdominal Distension	2	1
Abdominal Pain	2	2
Vomiting	2	2
Abdominal Pain Upper	1	2
Skin and Subcutaneous Tissue Disorders
Rash	3	2
Musculoskeletal, Connective Tissue and Bone Disorders
Arthralgia	9	11
Bone Pain	9	5
Myalgia	7	4
Back Pain	4	7
Musculoskeletal Stiffness	2	1
General Disorders and Administrative Site Conditions
Influenza-like Illness	11	6
Pyrexia	9	2
Fatigue	8	4
Rigors	8	1
Pain	5	4
Peripheral Edema	3	1
Asthenia	2	1

Laboratory Findings

In the Paget's disease trials, early, transient decreases in serum calcium and phosphate levels were observed. Approximately 21% of patients had serum calcium levels less than 8.4 mg/dL 9-11 days following Reclast administration.

Renal Impairment

In clinical trials in Paget's disease there were no cases of renal deterioration following a single 5 mg 15-minute infusion [see WARNINGS AND PRECAUTIONS].

Acute Phase Reaction

The signs and symptoms of acute phase reaction (influenza-like illness, pyrexia, myalgia, arthralgia, and bone pain) were reported in 25% of patients in the Reclast-treated group compared to 8% in the risedronate-treated group. Symptoms usually occur within the first 3 days following Reclast administration. The majority of these symptoms resolved within 4 days of onset.

Osteonecrosis Of The Jaw

Osteonecrosis of the jaw has been reported with zoledronic acid [see WARNINGS AND PRECAUTIONS].

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 Reclast:

Acute Phase Reactions

Fever, headache, flu-like symptoms, nausea, vomiting, diarrhea, 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, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and bronchoconstriction have been reported.

Asthma Exacerbations

Asthma exacerbations have been reported.

Hypocalcemia

Hypocalcemia has been reported.

Hypophosphatemia

Hypophosphatemia has been reported.

Osteonecrosis Of The Jaw

Osteonecrosis of the jaw 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 Reclast.

Ocular Adverse Events

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

Other

Hypotension in patients with underlying risk factors has been reported.

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4 mg/100 mL single-dose premixed bag

Mechanism of Action

The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In-vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.

Pharmacodynamics

Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of zoledronic acid are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion.

Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy.

Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone. In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous cell malignancies of the lung or head and neck or in genitourinary tumors such as renal cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.

Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma. Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels (corrected serum calcium, CSC) is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation [see Dosage and Administration (2.1)].

Pharmacokinetics

Pharmacokinetic data in patients with hypercalcemia 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 postinfusion 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 less than 1% of Cmax 24 hours postinfusion with population half-lives of t1/2α 0.24 hours and t1/2β 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 postinfusion, and a terminal elimination half-life t1/2γ 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 studies showed low affinity of zoledronic acid for the cellular components of human blood, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/mL to 5000 ng/mL. In-vitro, the plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/mL to 77% at 2000 ng/mL of zoledronic acid.

Metabolism

Zoledronic acid does not inhibit human P450 enzymes in-vitro. Zoledronic acid does not undergo biotransformation in-vivo. In animal studies, less than 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.

Excretion

In 64 patients with cancer and bone metastases, on average (± SD) 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 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 versus 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng x h/mL versus 420 ± 218 ng x h/mL). The difference between the AUC means was not statistically significant.

Special Populations

Pediatrics

Zoledronic Acid Injection is not indicated for use in children [see Use in Specific Populations (8.4)].

Geriatrics

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

Race

Population pharmacokinetic analyses did not indicate any differences in pharmacokinetics among Japanese and North American (Caucasian and African American) patients with cancer and bone metastases.

Hepatic Insufficiency

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

Renal Insufficiency

The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately impaired renal function. Compared to patients with normal renal function (N=37), patients with mild renal impairment (N=15) showed an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (N=11) showed an average increase in plasma AUC of 43%. Limited pharmacokinetic data are available for zoledronic acid in patients with severe renal impairment (creatinine clearance less than 30 mL/min). Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, which is doubled at a creatinine clearance of 10 mL/min. Creatinine clearance is calculated by the Cockcroft-Gault formula:

CrCl = [140-age (years)] x weight (kg) {x 0.85 for female patients}
            [72 x serum creatinine (mg/dL)]

Zoledronic acid systemic clearance in individual patients can be calculated from the population clearance of zoledronic acid, CL (L/h) = 6.5(CLcr/90)0.4. These formulae can be used to predict the zoledronic acid AUC in patients, where CL = Dose/AUC0-∞. The average AUC0-24 in patients with normal renal function was 0.42 mg•h/L and the calculated AUC0-∞ for a patient with creatinine clearance of 75 mL/min was 0.66 mg•h/L following a 4-mg dose of zoledronic acid. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed [see Warnings and Precautions (5.3)].