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pamidronate disodium injection Adverse Reactions

ADVERSE REACTIONS

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.

Clinical Studies

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. In the saline trial, 18% of patients had a temperature elevation of at least 1°C 24 to 48 hours after treatment.

Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on palpation) at the site of catheter insertion were most common 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 during the four U.S. controlled hypercalcemia clinical studies were reported to have had seizures, 2 of whom had preexisting seizure disorders. None of the seizures were considered to be drug-related by the investigators. However, a possible relationship between the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline arm 1 patient (4%) had a seizure.

There are no controlled clinical trials comparing the efficacy and safety of 90 mg pamidronate disodium over 24 hours to 2 hours in patients with hypercalcemia of malignancy. However, a comparison of data from separate clinical trials suggests that the overall safety profile in patients who received 90 mg pamidronate disodium over 24 hours is similar to those who received 90 mg pamidronate disodium over 2 hours. The only notable differences observed were an increase in the proportion of patients in the pamidronate disodium 24-hour group who experienced fluid overload and electrolyte/mineral abnormalities.

At least 15% of patients treated with pamidronate disodium for hypercalcemia of malignancy also experienced the following adverse events 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.

Many of these adverse experiences may have been related to the underlying disease state. The following table lists the adverse experiences considered to be treatment-related during comparative, controlled U.S. trials.

Treatment-Related Adverse Experiences Reported in Three U.S. Controlled Clinical Trials
Percent of Patients
Pamidronate Disodium
Etidronate Disodium Saline
60 mg over 4 hr60 mg over 24 hr90 mg over 24 hr7.5 mg/kg × 3 days
n=23n=73n=17n=35n=23

General

Edema01000
Fatigue001200
Fever26191890
Fluid overload00060
Infusion-site reaction041800
Moniliasis00600
Rigors00004

Gastrointestinal

Abdominal pain01000
Anorexia411200
Constipation40630
Diarrhea01000
Dyspepsia40000
Gastrointestinal hemorrhage00600
Nausea401860
Stomatitis01030
Vomiting40000

Respiratory

Dyspnea00030
Rales00600
Rhinitis00600
Upper respiratory infection03000

CNS

Anxiety00004
Convulsions00030
Insomnia01000
Nervousness00004
Psychosis40000
Somnolence01600
Taste perversion00030

Cardiovascular

Atrial fibrillation00604
Atrial flutter01000
Cardiac failure01000
Hypertension00604
Syncope00600
Tachycardia00604

Endocrine

Hypothyroidism00600

Hemic and Lymphatic

Anemia00600
Leukopenia40000
Neutropenia01000
Thrombocytopenia01000

Musculoskeletal

Myalgia01000

Urogenital

Uremia40000

Laboratory Abnormalities

Hypocalcemia011200
Hypokalemia441800
Hypomagnesemia4101234
Hypophosphatemia091830
Abnormal liver function00030

Paget’s Disease

Transient mild elevation of temperature >1°C above pretreatment baseline was noted within 48 hours after completion of treatment in 21% of the patients treated with 90 mg of pamidronate disodium in clinical trials.

Drug-related musculoskeletal pain and nervous system symptoms (dizziness, headache, paresthesia, increased sweating) were more common in patients with Paget’s disease treated with 90 mg of pamidronate disodium than in patients with hypercalcemia of malignancy treated with the same dose.

Adverse experiences considered to be related to trial drug, which occurred in at least 5% of patients with Paget’s disease treated with 90 mg of pamidronate disodium in two U.S. clinical trials, were fever, nausea, back pain, and bone pain.

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

Cardiovascular: Hypertension

Musculoskeletal: Arthrosis, bone pain

Nervous system: Headache

Most of these adverse experiences may have been related to the underlying disease state.

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

The most commonly reported (>15%) adverse experiences occurred with similar frequencies in the pamidronate disodium and placebo treatment groups, and most of these adverse experiences may have been related to the underlying disease state or cancer therapy.


Commonly Reported Adverse Experiences in Three U.S. Controlled Clinical Trials
Pamidronate Disodium
90 mg over 4 hours
PlaceboPamidronate Disodium
90 mg over 2 hours
PlaceboAll Pamidronate Disodium
90 mg
Placebo
N=205N=187N=367N=386N=572N=573
General%%%%%%
Asthenia16.117.125.619.222.218.5
Fatigue31.728.340.328.837.229.0
Fever38.53838.132.138.534
Metastases1.03.031.324.420.517.5
Pain13.211.815.018.114.316.1
Digestive System
Anorexia17.117.131.124.926.022.3
Constipation28.331.736.038.633.235.1
Diarrhea26.826.829.430.628.529.7
Dyspepsia17.613.418.315.022.617.5
Nausea35.637.463.559.153.551.8
Pain abdominal19.516.024.318.122.617.5
Vomiting16.619.846.339.135.732.8
Hemic and Lymphatic
Anemia47.841.739.536.842.538.4
Granulocytopenia20.515.519.320.519.818.8
Thrombocytopenia16.617.112.514.014.015.0
Musculoskeletal System
Arthralgias10.77.015.312.713.610.8
Myalgia25.415.026.422.52620.1
Skeletal Pain61.071.770.075.466.874
CNS
Anxiety7.89.118.016.814.314.3
Headache24.419.827.223.626.222.3
Insomnia17.117.225.119.422.219.0
Respiratory System
Coughing26.322.525.319.725.720.6
Dyspnea22.021.435.124.430.423.4
Pleural effusion2.94.315.09.110.77.5
Sinusitis14.616.616.110.415.612.0
Upper respiratory Tract Infection32.228.319.620.224.122.9
Urogenital System
Urinary Tract Infection15.69.120.217.618.515.6

Of the toxicities commonly associated with chemotherapy, the frequency of vomiting, anorexia, and anemia were slightly more common in the pamidronate disodium patients whereas stomatitis and alopecia occurred at a frequency similar to that in placebo patients. In the breast cancer trials, mild elevations of serum creatinine occurred in 18.5% of pamidronate disodium patients and 12.3% of placebo patients. Mineral and electrolyte disturbances, including hypocalcemia, were reported rarely and in similar percentages of pamidronate disodium-treated patients compared with those in the placebo group. The reported frequencies of hypocalcemia, hypokalemia, hypophosphatemia, and hypomagnesemia for pamidronate disodium-treated patients were 3.3%, 10.5%, 1.7%, and 4.4%, respectively, and for placebo-treated patients were 1.2%, 12%, 1.7%, and 4.5%, respectively. In previous hypercalcemia of malignancy trials, patients treated with pamidronate disodium (60 or 90 mg over 24 hours) developed electrolyte abnormalities more frequently (see ADVERSE REACTIONS, Hypercalcemia of Malignancy).

Arthralgias and myalgias were reported slightly more frequently in the pamidronate disodium group than in the placebo group (13.6% and 26% vs 10.8% and 20.1%, respectively).

In multiple myeloma patients, there were five pamidronate disodium-related serious and unexpected adverse experiences. Four of these were reported during the 12-month extension of the multiple myeloma trial. Three of the reports were of worsening renal function developing in patients with progressive multiple myeloma or multiple myeloma-associated amyloidosis. The fourth report was the adult respiratory distress syndrome developing in a patient recovering from pneumonia and acute gangrenous cholecystitis. One pamidronate disodium-treated patient experienced an allergic reaction characterized by swollen and itchy eyes, runny nose, and scratchy throat within 24 hours after the sixth infusion.

In the breast cancer trials, there were four pamidronate disodium-related adverse experiences, all moderate in severity, that caused a patient to discontinue participation in the trial. One was due to interstitial pneumonitis, another to malaise and dyspnea. One pamidronate disodium patient discontinued the trial due to a symptomatic hypocalcemia. Another pamidronate disodium patient discontinued therapy due to severe bone pain after each infusion, which the investigator felt was trial-drug-related.

Renal Toxicity

In a study of the safety and efficacy of pamidronate disodium 90 mg (2 hour infusion) versus Zometa® 4 mg (15 minute infusion) in bone metastases patients with multiple myeloma or breast cancer, renal deterioration was defined as an increase in serum creatinine of 0.5 mg/dL for patients with normal baseline creatinine (<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (≥ 1.4 mg/dL). The following are data on the incidence of renal deterioration in patients in this trial. See table below.

Incidence of Renal Function Deterioration in Multiple Myeloma and Breast Cancer Patients with Normal and Abnormal Serum Creatinine at Baseline*
Patient Population/Baseline CreatininePamidronate Disodium
90 mg/2 hours
Zometa®
4 mg/15 minutes
n/N (%) n/N (%)
*
Patients were randomized following the 15-minute infusion amendment for the Zometa® arm.
Zometa® is a registered trademark of Novartis.
Normal20/246 (8.1%) 23/246 (9.3%)
Abnormal 2/22 (9.1%) 1/26 (3.8%)
Total22/268 (8.2%) 24/272 (8.8%)

Post-Marketing Experience

The following adverse reactions have been reported during post-approval use of pamidronate disodium. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been reported in post-marketing use: 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 and occasionally incapacitating bone, joint, and/or muscle pain.

Cases of osteonecrosis (primarily involving the jaw) have 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. Data suggest a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged (See PRECAUTIONS).

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including pamidronate disodium (See PRECAUTIONS).

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