These highlights do not include all the information needed to use pamidronate disodium injection safely and effectively. See full prescribing information for pamidronate disodium injection. PAMIDRONATE DISODIUM injection, for intravenous use Initial U.S. Approval: 1991

Drug Labeling and Warnings

Drug Details [pdf]

PAMIDRONATE DISODIUM- pamidronate disodium injection, solution 
Teva Parenteral Medicines, Inc.

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FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Hypercalcemia of Malignancy

Pamidronate disodium injection is indicated for the treatment of moderate or severe hypercalcemia associated with malignancy, with or without bone metastases.

1.2 Paget’s Disease

Pamidronate disodium injection is indicated for the treatment of patients with moderate to severe Paget’s disease of bone.

1.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

Pamidronate disodium injection is indicated in conjunction with standard antineoplastic therapy, for the treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma [see Clinical Studies (14.3)].

1.4 Limitations of Use

The safety and efficacy of pamidronate disodium injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established.

2 DOSAGE AND ADMINISTRATION

2.1 Hypercalcemia of Malignancy

Vigorous saline hydration, should be initiated promptly along with pamidronate therapy and if possible the urine output should be about 2 L/day throughout treatment [see Warnings and Precautions (5.2)].

Patients who receive pamidronate disodium injection should have serum creatinine assessed prior to each treatment [see Warnings and Precautions (5.1)]. Treatment should be withheld for renal deterioration.

Moderate Hypercalcemia

The recommended dose of pamidronate disodium injection in moderate hypercalcemia (corrected serum calcium* of approximately 12 mg/dL to 13.5 mg/dL) is 60 mg to 90 mg given as a single-dose, intravenous infusion over 2 hours to 24 hours. Longer infusions (i.e., greater than 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal impairment.

Severe Hypercalcemia

The recommended dose of pamidronate disodium injection in severe hypercalcemia (corrected serum calcium* >13.5 mg/dL) is 90 mg given as a single-dose, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., greater than 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency/impairment.

*Albumin-corrected serum calcium = serum calcium, mg/dL + 0.8 (4-serum albumin, g/dL).

Retreatment

Retreatment with pamidronate disodium injection in patients who show complete or partial response initially may be carried out if serum calcium does not return to normal or remain normal after initial treatment. A minimum of 7 days between treatments is recommended to allow for full response to the initial dose. The dose and manner of retreatment is identical to that of the initial therapy.

2.2 Paget’s Disease

The recommended dose of pamidronate disodium injection in patients with moderate to severe Paget’s disease of bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg. When clinically indicated, patients should be retreated at the dose of initial therapy.

2.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

Osteolytic Bone Metastases of Breast Cancer

The recommended dose of pamidronate disodium injection in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every 3 to 4 weeks.

In a clinical study, renal deterioration was defined as follows:

• With normal baseline creatinine, an increase of 0.5 mg/dL.
• With abnormal baseline creatinine, an increase of 1 mg/dL.

In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

The optimal duration of therapy is not known; however, in two breast cancer studies, final analyses performed after 24 months of therapy demonstrated overall benefits [see Clinical Studies (14.3)].

Osteolytic Bone Lesions of Multiple Myeloma

The recommended dose of pamidronate disodium injection in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4-hour infusion administered every four weeks.

Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to pamidronate disodium injection infusion.

Limited information is available on the use of pamidronate disodium injection in multiple myeloma patients with a serum creatinine greater than or equal to 3 mg/dL.

Patients who receive pamidronate disodium injection should have serum creatinine assessed prior to each treatment. Treatment should be withheld for renal deterioration.

In a clinical study, renal deterioration was defined as follows:

• With normal baseline creatinine, an increase of 0.5 mg/dL.
• With abnormal baseline creatinine, an increase of 1 mg/dL.

In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

The optimal duration of therapy is not known. However, in a study of patients with myeloma, final analysis after 21 months demonstrated overall benefits [see Clinical Studies (14.3)].

2.5 Dilution for Administration

Hypercalcemia of Malignancy

The daily dose must be administered as an intravenous infusion over at least 2 hours and up to 24 hours for the 60 mg and 90 mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% sodium chloride injection or 5% dextrose injection. This infusion solution is stable for up to 24 hours at room temperature.

Paget’s Disease

The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% sodium chloride injection, or 5% dextrose injection and administered over a 4-hour period daily for 3 consecutive days.

Osteolytic Bone Metastases of Breast Cancer

The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9% sodium chloride injection or 5% dextrose injection and administered over a 2-hour period once every 3 to 4 weeks.

Osteolytic Bone Lesions of Multiple Myeloma

The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% sodium chloride injection, or 5% dextrose injection, and administered over a 4-hour period every four weeks.

2.6 Incompatibilities, Inspection before Use

Pamidronate disodium injection must not be mixed with calcium-containing infusion solutions such as Ringer’s solution. Administer as a single intravenous solution and infuse using an intravenous line reserved for pamidronate alone.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

3 DOSAGE FORMS AND STRENGTHS

Injection: 30 mg/10 mL solution in single-use vial

Injection: 90 mg/10 mL solution in single-use vial

4 CONTRAINDICATIONS

Pamidronate disodium is contraindicated in patients with hypersensitivity to pamidronate disodium, other bisphosphonates, or mannitol. Reactions to pamidronate disodium injection and to mannitol have included anaphylaxis.

5 WARNINGS AND PRECAUTIONS

5.1 Deterioration in Renal Function, Use in Patients with Renal Impairment

Bisphosphonates, such as pamidronate disodium, have been associated with renal toxicity, including focal segmental glomerulosclerosis. This toxicity has been manifested as nephritic syndrome, deterioration of renal function, and renal failure. Renal failure has been reported in patients after a single dose of pamidronate disodium. Some patients had gradual improvement in renal status after pamidronate disodium was discontinued.

Do not administer single doses of pamidronate disodium in excess of 90 mg due to the risk of clinically significant deterioration in renal function, [see Dosage and Administration (2.5)].

Assess serum creatinine prior to each treatment. Withhold treatment until renal function returns to baseline in patients who show evidence of deterioration in renal function. Do not administer pamidronate in patients with severe renal impairment for the treatment of bone metastases [see Dosage and Administration (2.1, 2.2, 2.3)].

5.2 Embryo-Fetal Toxicity

Bisphosphonates, such as pamidronate disodium, are incorporated into the bone matrix, and gradually released over periods of weeks to years. Pamidronate disodium may cause fetal harm when administered to a pregnant woman. In reproductive studies in rats and rabbits, pamidronate doses equivalent to 0.6 to 8.3 times the highest human recommended dose resulted in maternal toxicity and embryo/fetal effects.

There are no adequate and well-controlled studies of pamidronate disodium in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5.3 Electrolyte Disorders

Cases of asymptomatic hypophosphatemia (12%), hypokalemia (7%), hypomagnesemia (11%), and hypocalcemia (5% to 17%), were reported in pamidronate disodium-treated patients. Rare cases of symptomatic hypocalcemia (including tetany) have been reported in association with pamidronate disodium therapy. Monitor serum levels of calcium, phosphate, magnesium, and potassium, following initiation of therapy with pamidronate disodium. If hypocalcemia occurs, short-term calcium therapy may be necessary. In the absence of hypercalcemia, supplement with oral calcium and vitamin D in order to minimize the risk of hypocalcemia.

5.4 Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including pamidronate disodium. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of ONJ with certain tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Local infection including osteomyelitis has been reported with ONJ.

Patients receiving pamidronate should maintain good oral hygiene and have a dental examination with preventive dentistry prior to initiation of treatment.

While on treatment, avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [see Adverse Reactions (6.2)].

5.5 Atypical Fractures of the Femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including pamidronate disodium. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures may occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures also has been reported. A number of case reports noted that patients were receiving treatment also with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be evaluated for an atypical fracture. Consider discontinuation of pamidronate disodium therapy in patients suspected to have an atypical femur fracture pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.

6 ADVERSE REACTIONS

The following adverse reactions are described, or described in greater detail, in other sections:

• Deterioration in renal function [see Warnings and Precautions (5.1)]
• Electrolyte disorders [see Warnings and Precautions (5.3)]
• Osteonecrosis of the jaw [see Warnings and Precautions (5.4)]
• Atypical fractures of the femur [see Warnings and Precautions (5.5)]

6.1 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.

Hypercalcemia of Malignancy

Transient mild elevation of temperature by at least 1°C was noted 24 to 48 hours after administration of pamidronate disodium in 34% of patients in clinical trials. Local soft-tissue reactions (redness, swelling or induration and pain on palpation) at the site of catheter insertion were observed, most commonly in patients treated with 90 mg of pamidronate disodium. Symptomatic treatment resulted in rapid resolution in all patients.

Rare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one case of scleritis and one case of uveitis upon separate rechallenges.

Five of 231 patients (2%) who received pamidronate disodium while enrolled on controlled clinical trials for management of hypercalcemia were reported to have seizures, including two patients with pre-existing seizure disorders. One patient on the control (saline arm) also had a seizure. At least 15% of patients treated with pamidronate disodium for hypercalcemia of malignancy experienced the following adverse reactions during a clinical trial:

General: Fluid overload, generalized pain

Cardiovascular: Hypertension

Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting

Genitourinary: Urinary tract infection

Musculoskeletal: Bone pain

Laboratory abnormality: Anemia, hypokalemia, hypomagnesemia, hypophosphatemia

Table 1 lists the adverse reactions reported during comparative, controlled trials.

Table 1 Adverse Reactions Reported in Three U.S. Controlled Clinical Trials

	Percent of Patients
	Pamidronate Disodium			Etidronate Disodium	Saline
	60 mg	60 mg	90 mg	7.5 mg/kg
	over 4 hr	over 24 hr	over 24 hr	x 3 days
	n=23	n=73	n=17	n=35	n=23
General
Edema	0	1	0	0	0
Fatigue	0	0	12	0	0
Fever	26	19	18	9	0
Infusion-site reaction	0	4	18	0	0
Moniliasis	0	0	6	0	0
Gastrointestinal
Abdominal pain	0	1	0	0	0
Anorexia	4	1	12	0	0
Constipation	4	0	6	3	0
Diarrhea	0	1	0	0	0
Dyspepsia	4	0	0	0	0
Gastrointestinal hemorrhage	0	0	6	0	0
Nausea	4	0	18	6	0
Stomatitis	0	1	0	3	0
Vomiting	4	0	0	0	0
Respiratory
Rales	0	0	6	0	0
Rhinitis	0	0	6	0	0
Upper respiratory infection	0	3	0	0	0
CNS
Insomnia	0	1	0	0	0
Psychosis	4	0	0	0	0
Somnolence	0	1	6	0	0
Cardiovascular
Atrial fibrillation	0	0	6	0	4
Atrial flutter	0	1	0	0	0
Cardiac failure	0	1	0	0	0
Hypertension	0	0	6	0	4
Syncope	0	0	6	0	0
Tachycardia	0	0	6	0	4
Endocrine
Hypothyroidism	0	0	6	0	0
Hemic and Lymphatic
Anemia	0	0	6	0	0
Leukopenia	4	0	0	0	0
Neutropenia	0	1	0	0	0
Thrombocytopenia	0	1	0	0	0
Musculoskeletal
Myalgia	0	1	0	0	0
Urogenital
Uremia	4	0	0	0	0
Laboratory Abnormalities
Hypocalcemia	0	1	12	0	0
Hypokalemia	4	4	18	0	0
Hypomagnesemia	4	10	12	3	4
Hypophosphatemia	0	9	18	3	0

Paget’s Disease

Adverse reactions that occurred in at least 5% of patients with Paget’s disease treated with 90 mg of pamidronate disodium in two clinical trials included fever, nausea, back pain, and bone pain. Dizziness, headaches, parathesias, and increased sweating were also reported and occurred more frequently than reported in patients treated with pamidronate for hypercalcemia of malignancy.

At least 10% of all pamidronate disodium-treated patients with Paget’s disease also experienced the following adverse reactions during clinical trials:

Cardiovascular: Hypertension

Musculoskeletal: Arthrosis, bone pain

Nervous system: Headache

Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

The most commonly reported (>15%) adverse reactions occurred with similar frequencies in the pamidronate disodium and in the placebo group (see Table 2).

Table 2 Commonly Reported Adverse Reactions in Three U.S. Controlled Clinical Trials

	Pamidronate Disodium 90 mg over 4 hours	Placebo	Pamidronate Disodium 90 mg over 2 hours	Placebo	All Pamidronate Disodium 90 mg	Placebo
	N=205	N=187	N=367	N=386	N=572	N=573
	%	%	%	%	%	%
General
Asthenia	16	17	26	19	22	19
Fatigue	32	28	40	29	37	29
Fever	39	38	38	32	39	34
Metastases	1	3	31	24	21	18
Pain	13	12	15	18	14	16
Digestive System
Anorexia	17	17	31	25	26	22
Diarrhea	27	27	29	31	29	30
Dyspepsia	18	13	18	15	23	18
Nausea	36	37	64	59	54	52
Pain Abdominal	20	16	24	18	23	18
Vomiting	17	20	46	39	36	33
Hemic and Lymphatic
Anemia	48	42	40	37	43	38
Granulocytopenia	21	16	19	21	20	19
Musculoskeletal System
Arthralgias	11	7	15	13	14	11
Myalgia	25	15	26	23	26	20
Skeletal Pain	61	72	70	75	67	74
CNS
Anxiety	8	9	18	17	14	14
Headache	24	20	27	24	26	22
Insomnia	17	17	25	19	22	19
Respiratory System
Coughing	26	23	25	20	26	21
Dyspnea	22	21	35	24	30	23
Pleural Effusion	3	4	15	9	11	8
Sinusitis	15	17	16	10	16	12
Upper Respiratory Tract Infection	32	28	20	20	24	23
Urogenital System
Urinary Tract Infection	16	9	20	18	19	16

In the breast cancer trials, four pamidronate disodium-related adverse reactions, interstitial pneumonitis, malaise and dyspnea, symptomatic hypocalcemia, and severe bone pain, resulted in discontinuation of therapy.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval pamidronate sodium use. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General: reactivation of Herpes simplex and Herpes zoster, influenza-like symptoms

CNS: confusion and visual hallucinations, sometimes in the presence of electrolyte imbalance;

Skin: rash, pruritus

Special senses: conjunctivitis, orbital inflammation;

Renal and urinary disorders: focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome; renal tubular disorders (RTD); tubulointerstitial nephritis, and glomerulonephropathies.

Laboratory abnormalities: hyperkalemia, hypernatremia, hematuria. Rare instances of allergic manifestations have been reported, including hypotension, dyspnea, or angioedema, and, very rarely, anaphylactic shock. Pamidronate disodium is contraindicated in patients with clinically significant hypersensitivity to pamidronate disodium or other bisphosphonates (see CONTRAINDICATIONS).

Respiratory, thoracic and mediastinal disorders: adult respiratory distress syndrome (ARDS), interstitial lung disease (ILD).

Musculoskeletal and connective tissue disorders: severe, occasionally incapacitating bone, joint, and/or muscle pain.

7 DRUG INTERACTIONS

7.1 Nephrotoxic Drugs

Caution is indicated when pamidronate disodium is used with other potentially nephrotoxic drugs.

7.2 Thalidomide

In multiple myeloma patients, the risk of renal deterioration may be increased when pamidronate disodium is used in combination with thalidomide.

7.3 Loop Diuretics

Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of pamidronate disodium.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.2)]

Risk Summary

There are no adequate and well-controlled studies in pregnant women. Pamidronate disodium may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as pamidronate disodium, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. If pamidronate disodium is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, apprise the patient of the potential hazard to the fetus.

Animal Data

Intravenous bolus dosing of pregnant rats and rabbits with pamidronate resulted in maternal toxicity and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. Pamidronate can cross the placenta in rats, and has produced marked maternal and nonteratogenic embryo/fetal effects in both rats and rabbits.

8.3 Nursing Mothers

It is not known whether pamidronate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from pamidronate disodium, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness of pamidronate disodium in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of subjects in clinical studies of pamidronate disodium, approximately 20% were 65 and over, while approximately 15% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Females of Reproductive Potential

Contraception

Pamidronate disodium may cause fetal harm when administered during pregnancy. Advise females of reproductive potential to avoid becoming pregnant while taking pamidronate disodium. Since pamidronate disodium is incorporated into bone and is gradually released over periods of weeks to years, advise females of reproductive potential of the potential risk to a fetus if pregnancy occurs after completing treatment with this drug. If contraceptive methods are being considered, use effective contraception while taking and after taking pamidronate disodium. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking or after taking pamidronate disodium [see Use in Specific Populations (8.1)].

8.7 Patients with Renal Impairment

The renal clearance of pamidronate was reduced in patients with reduced creatinine clearance. Because pamidronate disodium is administered on a monthly basis, drug accumulation is not expected. No changes in pamidronate disodium dosing regimen are recommended for patients with mild to moderate renal impairment (creatinine clearance > 30 mL/min). Limited pharmacokinetic data exist in patients with creatinine clearance <30 mL/min [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

8.8 Patients with Hepatic Impairment

Patients with moderate hepatic impairment exhibited higher mean pamidronate AUC and Cmax. Because pamidronate disodium is administered on a monthly basis, drug accumulation is not expected. No changes in pamidronate disodium dosing regimen are recommended for patients with mild to moderate hepatic impairment. Pamidronate disodium has not been studied in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Several cases of drug overdose have been reported in hypercalcemia patients treated with total doses of 225 mg to 300 mg pamidronate disodium given over 2.5 to 4 days. All patients survived, but all developed hypocalcemia that required intravenous and/or oral administration of calcium. If overdosage occurs, treat symptomatic hypocalcemia patients with short-term intravenous calcium.

Single doses of pamidronate disodium should not exceed 90 mg, and the duration of the intravenous infusion should be no less than 2 hours [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)].

In addition, one obese woman (95 kg) who was treated with 285 mg of pamidronate disodium/day for 3 days experienced high fever (39.5°C), hypotension (from 170/90 mmHg to 90/60 mmHg), and transient taste perversion, occurring about 6 hours after the first infusion. Fever and hypotension rapidly reversed with steroid therapy.

11 DESCRIPTION

Pamidronate disodium injection is a sterile bisphosphonate available in 30 mg or 90 mg vials for intravenous administration. Each mL of the 30 mg vial contains: 3 mg pamidronate disodium; 47 mg mannitol USP; water for injection, USP, q.s.; phosphoric acid to adjust pH 6.5. Each mL of the 90 mg vial contains: 9 mg pamidronate disodium; 37.5 mg mannitol USP; water for injection, USP, q.s.; phosphoric acid to adjust pH to 6.5.

The pH of a 1% solution of pamidronate disodium in distilled water is approximately 8.3. Pamidronate disodium, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt, pentahydrate, and its structural formula is:

C3H9NO7P2Na25H2O M.W. 369.1

Pamidronate disodium is a white to practically white powder. It is soluble in water and in 2N sodium hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic acid, and practically insoluble in organic solvents.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The principal pharmacologic action of pamidronate disodium is inhibition of bone resorption. Although the mechanism of antiresorptive action is not completely understood, several factors are thought to contribute to this action. Pamidronate disodium adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may block dissolution of this mineral component of bone. In vitro, pamidronate disodium inhibited osteoclast activity. In animal studies, pamidronate disodium inhibited bone resorption, but did not inhibit bone formation and mineralization. In animal tumor models, pamidronate disodium inhibited the increased osteoclast activity induced by tumors.

12.2 Pharmacodynamics

Serum phosphate levels have been noted to decrease after administration of pamidronate disodium, presumably because of decreased release of phosphate from bone and increased renal excretion as parathyroid hormone levels, which are usually suppressed in hypercalcemia associated with malignancy, return toward normal. Phosphate therapy was administered in 30% of the patients in response to a decrease in serum phosphate levels. Phosphate levels usually returned toward normal within 7 to 10 days.

Urinary calcium/creatinine and urinary hydroxyproline/creatinine ratios decrease and usually return to within or below normal after treatment with pamidronate disodium. These changes occur within the first week after treatment, as do decreases in serum calcium levels, and are consistent with an antiresorptive pharmacologic action.

12.3 Pharmacokinetics

Table 3 shows maximum concentration, percent of dose excreted in urine, total clearance, and renal clearance of pamidronate after an intravenous infusion of 30, 60, or 90 mg of pamidronate disodium over 4 hours and 90 mg of pamidronate disodium over 24 hours in cancer patients (n=24) who had minimal or no bony involvement.

Table 3 Mean (Standard Deviation, CV%) Pamidronate Pharmacokinetic Parameters in Cancer Patients (n=6 for each group)

Dose (infusion rate)	Maximum Concentration (mcg/mL)	Percent of dose excreted in urine	Total Clearance (mL/min)	Renal Clearance (mL/min)
30 mg	0.73	43.9	136	58
(4 hrs)	(0.14, 19.1%)	(14, 31.9%)	(44, 32.4%)	(27, 46.5%)
60 mg	1.44	47.4	88	42
(4 hrs)	(0.57, 39.6%)	(47.4, 54.4%)	(56, 63.6%)	(28, 66.7%)
90 mg	2.61	45.3	103	44
(4 hrs)	(0.74, 28.3%)	(25.8, 56.9%)	(37, 35.9%)	(16, 36.4%)
90 mg	1.38	47.5	101	52
(24 hrs)	(1.97, 142.7%)	(10.2, 21.5%)	(58, 57.4%)	(42, 80.8%)

Distribution

The body retention of pamidronate was 54 ± 16% (mean ± standard deviation) of the dose over 120 hours.

Metabolism

Pamidronate is not metabolized.

Elimination

The elimination half-life is 28 ± 7 hours (mean ± standard deviation). Total and renal clearances of pamidronate were 107 ± 50 mL/min and 49 ± 28 mL/min, respectively. The rate of elimination from bone has not been determined.

After administration of 30, 60, and 90 mg of pamidronate disodium over 4 hours, and 90 mg of pamidronate disodium over 24 hours, 46 ± 16% (mean ± standard deviation) of the drug was excreted unchanged in the urine within 120 hours. Cumulative urinary excretion was linearly related to dose.

Specific Populations

Renal Impairment

The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and varying degrees of renal impairment. Each patient received a single 90 mg dose of pamidronate disodium infused over 4 hours. Renal clearance correlated with creatinine clearance (see Figure 1). Because pamidronate disodium is administered on a monthly basis, drug accumulation is not expected.

Figure 1: Pamidronate renal clearance as a function of creatinine clearance in patients with normal and impaired renal function. The lines are the mean prediction line and 95% confidence intervals.

Hepatic Impairment

The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone metastases with normal hepatic function (n=6) and mild to moderate hepatic dysfunction (n=7). Each patient received a single 90 mg dose of pamidronate disodium infused over 4 hours. Although there was a difference in the pharmacokinetics between patients with normal and impaired hepatic function, the difference was not considered clinically relevant. Patients with hepatic impairment exhibited higher mean AUC (53% increase) and Cmax (29% increase), and decreased plasma clearance (33% decrease) values. Because pamidronate disodium is administered on a monthly basis, drug accumulation is not expected.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study with daily oral administration of pamidronate in rats, there was a positive dose-response relationship for benign adrenal pheochromocytoma. The lowest daily dose associated with adrenal pheochromocytoma resulted in systemic exposures that were similar to the systemic exposure achieved in patients at the intended clinical dose. Adrenal pheochromocytoma also was observed in low numbers in the control animals and is considered a relatively common spontaneous neoplasm in the rat. Pamidronate given daily by oral administration was not carcinogenic in an 80 week study in mice.

Pamidronate did not cause genetic toxicity in the Ames bacterial mutagenicity assay, nucleus-anomaly test, sister-chromatid-exchange study, point-mutation test and micronucleus test in the rat.

In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg/kg of pamidronate orally; however, this occurred only when animals were mated with members of the same dose group.

13.2 Animal Toxicology and/or Pharmacology

After intravenous administration of radiolabeled pamidronate in rats, approximately 50% to 60% of the compound was rapidly adsorbed by bone and slowly eliminated from the body by the kidneys. In rats given 10 mg/kg bolus injections of radiolabeled pamidronate disodium, approximately 30% of the compound was found in the liver shortly after administration and was then redistributed to bone or eliminated by the kidneys over 24 to 48 hours. Studies in rats injected with radiolabeled pamidronate disodium showed that the compound was rapidly cleared from the circulation and taken up mainly by bones, liver, spleen, teeth, and tracheal cartilage. Radioactivity was eliminated from most soft tissues within 1 to 4 days; was detectable in liver and spleen for 1 and 3 months, respectively; and remained high in bones, trachea, and teeth for 6 months after dosing. Bone uptake occurred preferentially in areas of high bone turnover. The terminal phase of elimination half-life in bone was estimated to be approximately 300 days.

14 CLINICAL STUDIES

14.1 Hypercalcemia of Malignancy

In one double-blind clinical trial, 52 patients who had hypercalcemia of malignancy received 30 mg, 60 mg, or 90 mg of pamidronate disodium as a single 24-hour intravenous infusion if their corrected serum calcium levels were ≥ 12 mg/dL after 48-hours of saline hydration (See Table 4).

Table 4: Comparison of Calcium Normalization Following a 24-hour Infusion of Pamidronate Disodium

Pamidronate Disodium	30 mg	60 mg	90 mg
Mean Baseline Corrected Serum Calcium (after 48 hours saline hydration)	13.8 mg/dL	13.8 mg/dL	13.3 mg/dL
% Patients with Normalized Serum Calcium (N=52)
Day 7	41%	61%	100%
Day 14	----	33%	53%

In a second double-blind, controlled clinical trial, 65 cancer patients who had corrected serum calcium levels of ≥12 mg/dL after at least 24-hours of saline hydration were randomized to receive either 60 mg of pamidronate disodium as a single 24-hour intravenous infusion or 7.5 mg/kg of etidronate disodium as a 2-hour intravenous infusion daily for 3 days. Results are shown in Table 5.

Table 5: Calcium Levels, Percentage of Patients with Response over Time, and Median Duration of Response

	Pamidronate Disodium; 60 mg/24-hours; (N=30)	Etidronate Disodium; 7.5 mg/kg/2-hours; (N=35)	P-value
Mean Corrected Serum Calcium Level
Baseline	14.6 mg/dL	13.8 mg/dL
At Day 7	10.4 mg/dL	11.2 mg/dL
% Patients with Normalized Serum Calcium Level or > 15% from Baseline
At Day 7	97%	65%	P< 0.01
At Day 14	43%	18%
Median Duration of Response
	7 days	5 days

In a third multicenter, randomized, parallel, double-blind trial, 69 patients with cancer, who had a corrected serum calcium level of ≥ 12 mg/dL after 24 hours of saline hydration, received 60 mg of pamidronate disodium as a 4- or 24-hour infusion or a saline control (Table 6).

Table 6: Comparison of Pamidronate Disodium 4-hour, 24-hours Infusion with Saline Control

	Pamidronate Disodium; 60 mg/4 hours		Pamidronate Disodium; 60 mg/24 hours	Saline Control
Baseline Corrected; Serum Calcium	14.2 mg/dL		13.7 mg/dL	13.7 mg/dL
% Patients with Normalized Serum Calcium (N=69)
At Day 7	78%	61%		22%
At Day 14	39%	26%		---
Median Duration of Complete Response
Days	4	6.5

In all three trials, similar response rates were observed with pamidronate disodium treatment regardless of the presence or absence of bone metastases. Concomitant administration of furosemide did not affect response rates.

Thirty-two patients who had recurrent or refractory hypercalcemia of malignancy were given a second course of 60 mg of pamidronate disodium over a 4- or 24-hour period. Of these, 41% showed a complete response and 16% showed a partial response to the retreatment, and these responders had about a 3 mg/dL fall in mean-corrected serum calcium levels 7 days after retreatment.

In a fourth multicenter, randomized, double-blind trial, 103 patients with cancer and hypercalcemia (corrected serum calcium ≥12 mg/dL) received 90 mg of pamidronate disodium as a 2-hour infusion. The mean baseline corrected serum calcium was 14 mg/dL. Patients were not required to receive IV hydration prior to drug administration, but all subjects did receive at least 500 mL of IV saline hydration concomitantly with the pamidronate infusion. By day 10 after drug infusion, 70% of patients had normal corrected serum calcium levels (<10.8 mg/dL).

14.2 Paget’s Disease

In a double-blind clinical trial, 64 patients with moderate to severe Paget’s disease of bone received 5 mg, 15 mg, or 30 mg of pamidronate disodium as a single 4-hour infusion daily on 3 consecutive days, for total doses of 15 mg, 45 mg, and 90 mg of pamidronate disodium.

For the 15 mg, 45 mg, and 90 mg groups, mean baseline serum alkaline phosphatase levels were 1409 U/L, 983 U/L, and 1085 U/L, and mean baseline urine hydroxyproline/creatinine ratios were 0.25, 0.19, and 0.19, respectively.

The effects of pamidronate disodium on serum alkaline phosphatase (SAP) and urine hydroxyproline/creatinine ratios (UOHP/C) are summarized in Table 7.

Table 7 Percent of Patients with Decrease in SAP and UOHP/C

SAP				UOHP/C
% Decrease	15 mg	45 mg	90 mg	15 mg	45 mg	90 mg
≥50	26%	33%	60%	15%	47%	72%
≥30	40%	65%	83%	35%	57%	85%

For the 15 mg, 45 mg, and 90 mg groups, median maximum percent decreases from baseline in serum alkaline phosphatase were 25%, 41%, and 57%, and urine hydroxyproline/creatinine ratios were 25%, 47%, and 61%, respectively. The median time to response (≥50% decrease) for serum alkaline phosphatase was approximately 1 month for the 90 mg group, and the response duration ranged from 1 to 372 days.

Twenty-five patients who had Paget’s disease were retreated with 90 mg of pamidronate disodium. Of these, 44% had a ≥50% decrease in serum alkaline phosphatase from baseline after treatment, and 39% had a ≥50% decrease in urine hydroxyproline/creatinine ratio from baseline after treatment.

14.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

Breast Cancer

Two double-blind, randomized, placebo-controlled trials compared the safety and efficacy of pamidronate disodium 90 mg infused over 2 hours every 3 to 4 weeks for 24 months to placebo for prevention of SREs in breast cancer patients with osteolytic bone metastases who had one or more predominantly lytic metastases of at least 1 cm in diameter. The first trial enrolled 382 patients receiving chemotherapy, of whom 185 were randomized to pamidronate disodium and 197 to placebo. The second trial enrolled 372 patients receiving hormonal therapy, of whom 182 were randomized to pamidronate disodium and 190 to placebo. All but three patients were evaluable for efficacy. Bone lesion response was radiographically assessed at baseline and at 3, 6, and 12 months. Therapy continued for 24 months unless patient discontinued study.

Median duration of follow-up was 13 months in patients receiving chemotherapy and 17 months in patients receiving hormone therapy. Twenty-five percent of the patients in the chemotherapy study and 37% of the patients in the hormone therapy study received pamidronate disodium for 24 months. Efficacy results are shown in Table 8:

Table 8 Efficacy Results in Breast Cancer Patients

* Fractures and radiation to bone were two of several secondary endpoints. The statistical significance of these analyses may be overestimated since numerous analyses were performed. † NR = Not Reached
N	Breast Cancer Patients Receiving Chemotherapy
	Any SRE		Radiation		Fractures
	Pamidronate disodium	Placebo	Pamidronate disodium	Placebo	Pamidronate disodium	Placebo
	185	195	185	195	185	195
Skeletal Morbidity Rate; (#SRE/year); Mean	2.5	3.7	0.8	1.3	1.6	2.2
P-Value	<.001		<.001*		.018*
Proportion of patients having an SRE	46%	65%	28%	45%	36%	49%
P-Value	<.001		<.001*		.014*
Median Time to SRE (months)	13.9	7	NR†	14.2	25.8	13.3
P-Value	<.001		<.001*		.009*
N	Breast Cancer Patients Receiving Hormonal Therapy
	Any SRE		Radiation		Fractures
	Pamidronate disodium	Placebo	Pamidronate disodium	Placebo	Pamidronate disodium	Placebo
	182	189	182	189	182	189
Skeletal Morbidity Rate; (#SRE/year); Mean	2.4	3.6	0.6	1.2	1.6	2.2
P-Value	.021		.013*		.040*
Proportion of patients having an SRE	55%	63%	31%	40%	45%	55%
P-Value	.094		.058*		.054*
Median Time to SRE (months)	10.9	7.4	NR†	23.4	20.6	12.8
P-Value	.118		.016*		.113*

Advanced Multiple Myeloma

In a double-blind, randomized, placebo-controlled trial, 392 patients on therapy for advanced multiple myeloma received pamidronate disodium or placebo to determine the effect on the occurrence of skeletal-related events (SREs). SREs were defined as the occurrence of new or additional pathologic fractures, radiation therapy or surgery for bony fracture, impending fracture, or spinal cord compression. Pamidronate disodium 90 mg or placebo was administered as a 4-hour infusion every 4 weeks for 9 months. Of the 392 patients enrolled, 377 were evaluable for efficacy. Results are shown in Table 9.

Table 9: SRE Outcomes in Multiple Myeloma

	Pamidronate disodium 90 mg /4 hours (N=196)	Placebo (N=181)	P-value
At 1 year; % of Patients with SRE	24%	41%	P< 0.001
% with Pathological Fracture	17%	30%	P<0.004
% with Radiation to Bone	14%	21%	P<0.049
At 1.75 years (21 Months); % Pathologic Vertebral Fractures	16%	27%	P=0.005

The times to the first SRE occurrence, pathologic fracture, and radiation to bone were significantly longer in the pamidronate disodium group (P=0.001, 0.006, and 0.046, respectively). After 21 months, the proportion of patients experiencing any skeletal event remained significantly less in the pamidronate disodium group compared to the placebo group (P=0.015). Time to first SRE was significantly longer in the pamidronate disodium group compared to placebo (P=0.016). Survival was not different between treatment groups.

16 HOW SUPPLIED/STORAGE AND HANDLING

Pamidronate Disodium Injection is available as follows:

NDC Number	Strength	Size
0703-4075-51	30 mg per 10 mL	single-use vial (3 mg/mL)	Packaged individually
0703-4085-51	90 mg per 10 mL	single-use vial (9 mg/mL)	Packaged individually

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

• Inform female patients that pamidronate can cause fetal harm when administered to a pregnant woman. Advise patients to avoid becoming pregnant and to report any pregnancies while receiving or after cessation of pamidronate therapy [see Warnings and Precautions (5.2)].
• Inform patients that the risk of osteonecrosis of the jaw is increased in patients undergoing invasive dental procedures. Advise patients to avoid such procedures, if possible, and to maintain good dental hygiene and routine dental care [see Warnings and Precautions (5.4)].
• Inform patients that atypical femur fractures have occurred in patients taking bisphosphonates. Advise patients to report any thigh or groin pain [see Warnings and Precautions (5.5)].

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. C 12/2014

Package/Label Display Panel

Pamidronate Disodium Injection 30 mg/10 mL, Single-Use Vial, Carton Text

NDC: 0703-4075-51       Rx only

Pamidronate
Disodium Injection

30 mg/10 mL

(3 mg/mL)

For Intravenous Infusion

Do not mix with
calcium-containing
infusion solutions.

Sterile

Single-Use Vial

TEVA

Package/Label Display Panel

Pamidronate Disodium Injection 90 mg/10 mL, Single-Use Vial, Carton Text

NDC: 0703-4085-51       Rx only

Pamidronate
Disodium Injection

90 mg/10 mL

(9 mg/mL)

For Intravenous Infusion

Do not mix with
calcium-containing
infusion solutions.

Sterile

Single-Use Vial

TEVA

PAMIDRONATE DISODIUM 
pamidronate disodium injection, solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 0703-4075
Route of Administration	INTRAVENOUS

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
PAMIDRONATE DISODIUM (UNII: 8742T8ZQZA) (PAMIDRONIC ACID - UNII:OYY3447OMC)	PAMIDRONATE DISODIUM	3 mg  in 1 mL

Inactive Ingredients
Ingredient Name	Strength
MANNITOL (UNII: 3OWL53L36A)
WATER (UNII: 059QF0KO0R)
PHOSPHORIC ACID (UNII: E4GA8884NN)

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 0703-4075-51	1 in 1 CARTON	11/08/2005	11/08/2005
1		10 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076153	04/01/2002	11/08/2005

PAMIDRONATE DISODIUM 
pamidronate disodium injection, solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 0703-4085
Route of Administration	INTRAVENOUS

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
PAMIDRONATE DISODIUM (UNII: 8742T8ZQZA) (PAMIDRONIC ACID - UNII:OYY3447OMC)	PAMIDRONATE DISODIUM	9 mg  in 1 mL

Inactive Ingredients
Ingredient Name	Strength
MANNITOL (UNII: 3OWL53L36A)
WATER (UNII: 059QF0KO0R)
PHOSPHORIC ACID (UNII: E4GA8884NN)

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 0703-4085-51	1 in 1 CARTON	11/08/2005	09/30/2012
1		10 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076153	04/01/2002	09/30/2012

Labeler - Teva Parenteral Medicines, Inc. (794362533)

Revised: 9/2019

Document Id: 73277e9a-6f80-47e3-9987-a54ce801b799

34391-3

Set id: d3f15563-21af-4e0d-a9f1-1ebc596c848f

Version: 11

Effective Time: 20190919