Pamidria

Pamidria uses

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Pamidria reviews

INDICATIONS AND USAGE

Hypercalcemia of Malignancy

Pamidria for Injection USP, in conjunction with adequate hydration, is indicated for the treatment of moderate or severe hypercalcemia associated with malignancy, with or without bone metastases. Patients who have either epidermoid or non-epidermoid tumors respond to treatment with Pamidria for Injection USP. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures. Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia. The safety and efficacy of Pamidria for Injection USP in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established.

Paget's Disease

Pamidria for Injection USP is indicated for the treatment of patients with moderate to severe Paget’s disease of bone. The effectiveness of Pamidria for Injection USP was demonstrated primarily in patients with serum alkaline phosphatase ≥3 times the upper limit of normal. Pamidria for Injection USP therapy in patients with Paget’s disease has been effective in reducing serum alkaline phosphatase and urinary hydroxyproline levels by ≥50% in at least 50% of patients, and by ≥30% in at least 80% of patients. Pamidria for Injection USP therapy has also been effective in reducing these biochemical markers in patients with Paget’s disease who failed to respond, or no longer responded to other treatments.

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

Pamidria for Injection USP is indicated, in conjunction with standard antineoplastic therapy, for the treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. The Pamidria for Injection USP treatment effect appeared to be smaller in the study of breast cancer patients receiving hormonal therapy than in the study of those receiving chemotherapy, however, overall evidence of clinical benefit has been demonstrated.

CONTRAINDICATIONS

Pamidria for Injection USP is contraindicated in patients with clinically significant hypersensitivity to Pamidria for Injection USP or other bisphosphonates.

WARNINGS

Deterioration in Renal Function

Bisphosphonates, including Pamidria, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure.

DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF Pamidria SHOULD NOT EXCEED 90 MG. Renal deterioration, progression to renal failure, and dialysis have been reported in patients after the initial or a single dose of Pamidria.

Focal segmental glomerulosclerosis (including the collapsing variant) with or without nephrotic syndrome, which may lead to renal failure, has been reported in pamidronate disodium-treated patients, particularly in the setting of multiple myeloma and breast cancer. Some of these patients had gradual improvement in renal status after Pamidria was discontinued.

Patients who receive Pamidria should have serum creatinine assessed prior to each treatment. Patients treated with Pamidria for bone metastases should have the dose withheld if renal function has deteriorated.

PREGNANCY

Bisphosphonates, such as Pamidria, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. Pamidria 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 Pamidria 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

PRECAUTIONS

General

Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, magnesium, and potassium, should be carefully monitored following initiation of therapy with Pamidria. Cases of asymptomatic hypophosphatemia, hypokalemia (7%), hypomagnesemia (11%), and hypocalcemia (5%-12%), were reported in pamidronate disodium-treated patients. Rare cases of symptomatic hypocalcemia (including tetany) have been reported in association with Pamidria therapy. If hypocalcemia occurs, short-term calcium therapy may be necessary. In Paget’s disease of bone, 17% of patients treated with 90 mg of Pamidria showed serum calcium levels below 8 mg/dL.

Patients with a history of thyroid surgery may have relative hypoparathyroidism that may predispose to hypocalcemia with Pamidria.

Renal Insufficiency

Pamidria is excreted intact primarily via the kidney, and the risk of renal adverse reactions may be greater in patients with impaired renal function. Patients who receive Pamidria should have serum creatinine assessed prior to each treatment. In patients receiving Pamidria for bone metastases, who show evidence of deterioration in renal function, Pamidria treatment should be withheld until renal function returns to baseline.

In clinical trials, patients with renal impairment (serum creatinine >3.0 mg/dL) have not been studied. Limited pharmacokinetic data exist in patients with creatinine clearance <30 ml/min For the treatment of bone metastases, the use of Pamidria in patients with severe renal impairment is not recommended. In other indications, clinical judgment should determine whether the potential benefit outweighs the potential risk in such patients.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Pamidria. 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 reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis.

Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.

While on treatment, these patients should 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.

Musculoskeletal Pain

In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. This category of drugs includes Pamidria for Injection USP. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

Atypical Fractures of the Femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Pamidria. 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 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 has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids 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 suspected of having an atypical fracture and should be evaluated. Discontinuation of Pamidria USP therapy in patients suspected to have an atypical femur fracture should be considered 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.

Laboratory Tests

Patients who receive Pamidria USP should have serum creatinine assessed prior to each treatment. Serum calcium, electrolytes, phosphate, magnesium, and CBC, differential, and hematocrit/hemoglobin must be closely monitored in patients treated with Pamidria USP. Patients who have preexisting anemia, leukopenia, or thrombocytopenia should be monitored carefully in the first 2 weeks following treatment. Patients receiving Pamidria USP may be at risk for anemia, leukopenia or thrombocytopenia and should have regular hematology assessments.

Drug Interactions

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

Caution is indicated when Pamidria USP is used with other potentially nephrotoxic drugs.

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

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 in males. Although this condition was also observed in females, the incidence was not statistically significant. When the dose calculations were adjusted to account for the limited oral bioavailability of pamidronate in rats, systemic exposure with the lowest daily dose associated with adrenal pheochromocytoma resulted in systemic exposures that were similar to the systemic exposure achieved at the intended clinical dose. Adrenal pheochromocytoma was also 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 was nonmutagenic in six mutagenicity assays, including: the Ames bacterial mutagenicity assay (with and without metabolic activation), 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. Pamidronate has not been administered intravenously in such a study.

Animal Toxicology

In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) administration of pamidronate.

Two 7-day intravenous infusion studies were conducted in the dog wherein pamidronate was given for 1, 4, or 24 hours at doses of 1-20 mg/kg for up to 7 days. In the first study, the compound was well tolerated at 3 mg/kg (1.7 x highest recommended human dose [HRHD] for a single intravenous infusion) when administered for 4 or 24 hours, but renal findings such as elevated BUN and creatinine levels and renal tubular necrosis occurred when 3 mg/kg was infused for 1 hour and at doses of ≥10 mg/kg. In the second study, slight renal tubular necrosis was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional findings included elevated BUN levels in several treated animals and renal tubular dilation and/or inflammation at ≥1 mg/kg after each infusion time.

Pamidronate was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6, and 20 mg/kg as a 1-hour infusion, once a week, for 3 months followed by a 1-month recovery period. In rats, nephrotoxicity was observed at ≥6 mg/kg and included increased BUN and creatinine levels and tubular degeneration and necrosis. These findings were still present at 20 mg/kg at the end of the recovery period. In dogs, moribundity/death and renal toxicity occurred at 20 mg/kg as did kidney findings of elevated BUN and creatinine levels at ≥6 mg/kg and renal tubular degeneration at ≥4 mg/kg. The kidney changes were partially reversible at 6 mg/kg. In both studies, the dose level that produced no adverse renal effects was considered to be 2 mg/kg (1.1 x HRHD for a single intravenous infusion).

Pregnancy Category D

There are no adequate and well-controlled studies in pregnant women.

Pamidria USP may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as Pamidria, 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 Pamidria USP is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus.

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.

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 Pamidria USP, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

Geriatric Use

Of the total number of subjects in clinical studies of Pamidria, 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.

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 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 Pamidria 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 at the site of catheter insertion were most common in patients treated with 90 mg of Pamidria. 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 Pamidria 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 Pamidria 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 Pamidria over 24 hours is similar to those who received 90-mg Pamidria over 2 hours. The only notable differences observed were an increase in the proportion of patients in the Pamidria 24-hour group who experienced fluid overload and electrolyte/ mineral abnormalities.

At least 15% of patients treated with Pamidria 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.

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 Pamidria 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 Pamidria 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 Pamidria 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 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.

Of the toxicities commonly associated with chemotherapy, the frequency of vomiting, anorexia, and anemia were slightly more common in the Pamidria 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 Pamidria 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 Pamidria (60 or 90 mg over 24 hours) developed electrolyte abnormalities more frequently.

Arthralgias and myalgias were reported slightly more frequently in the Pamidria 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 Pamidria patient discontinued the trial due to a symptomatic hypocalcemia. Another Pamidria 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 Pamidria 90 mg (2-hour infusion) vs 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.

Post-Marketing Experience

The following adverse reactions have been reported during post-approval use of Pamidria. 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. Pamidria for Injection USP is contraindicated in patients with clinically significant hypersensitivity to Pamidria or other bisphosphonates. 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 Pamidria. 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.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including Pamidria.

OVERDOSAGE

There have been several cases of drug maladministration of intravenous Pamidria in hypercalcemia patients with total doses of 225 mg to 300 mg given over 2 ½ to 4 days. All of these patients survived, but they experienced hypocalcemia that required intravenous and/or oral administration of calcium. Single doses of Pamidria USP should not exceed 90 mg and the duration of the intravenous infusion should be no less than 2 hours.

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, noted about 6 hours after the first infusion. The fever and hypotension were rapidly corrected with steroids.

If overdosage occurs, symptomatic hypocalcemia could also result; such patients should be treated with short-term intravenous calcium.

DOSAGE AND ADMINISTRATION

Hypercalcemia of Malignancy

Consideration should be given to the severity of as well as the symptoms of hypercalcemia. Vigorous saline hydration alone may be sufficient for treating mild, asymptomatic hypercalcemia. Overhydration should be avoided in patients who have potential for cardiac failure. In hypercalcemia associated with hematologic malignancies, the use of glucocorticoid therapy may be helpful.

Moderate Hypercalcemia

The recommended dose of Pamidria for Injection USP in moderate hypercalcemia is 60 to 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.

Severe Hypercalcemia

The recommended dose of Pamidria for Injection USP 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., >2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.

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*Albumin-corrected serum calcium (CCa,mg/dL) = serum calcium, mg/dL + 0.8 (4.0-serum albumin, g/dL).

Retreatment

A limited number of patients have received more than one treatment with Pamidria for hypercalcemia. Retreatment with Pamidria for Injection USP, 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. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. The dose and manner of retreatment is identical to that of the initial therapy.

Paget's Disease

The recommended dose of Pamidria for Injection USP 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.

Retreatment

A limited number of patients with Paget’s disease have received more than one treatment of Pamidria in clinical trials. When clinically indicated, patients should be retreated at the dose of initial therapy.

Osteolytic Bone Lesions of Multiple Myeloma

The recommended dose of Pamidria for Injection USP in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4-hour infusion given on a monthly basis.

Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to Pamidria for Injection USP infusion.

Limited information is available on the use of Pamidria for Injection USP in multiple myeloma patients with a serum creatinine ≥3.0 mg/dL.

Patients who receive Pamidria for Injection USP 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:

• For patients with normal baseline creatinine, increase of 0.5 mg/dL.
• For patients with abnormal baseline creatinine, increase of 1 mg/dL.

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

The optimal duration of therapy is not yet known, however, in a study of patients with myeloma, final analysis after 21 months demonstrated overall benefits.

Osteolytic Bone Metastases of Breast Cancer

The recommended dose of Pamidria for Injection USP in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every 3-4 weeks.

Pamidria has been frequently used with doxorubicin, fluorouracil, cyclophosphamide, methotrexate, mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine, megesterol, and tamoxifen. It has been given less frequently with etoposide, cisplatin, cytarabine, paclitaxel, and aminoglutethimide.

Patients who receive Pamidria for Injection USP 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:

• For patients with normal baseline creatinine, increase of 0.5 mg/dL.
• For patients with abnormal baseline creatinine, increase of 1 mg/dL.

In this clinical study, Pamidria 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.

Calcium and Vitamin D Supplementation

In the absence of hypercalcemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or vitamin D deficiency, and patients with Paget’s disease of the bone, should be given oral calcium and vitamin D supplementation in order to minimize the risk of hypocalcemia.

Preparation of Solution

Reconstitution

Pamidria for Injection USP is reconstituted by adding 10 mL of Sterile Water for Injection, USP, to each vial, resulting in a solution of 30 mg/10 mL, 60mg/10mL or 90 mg/10 mL. The pH of the reconstituted solution is 6.0-7.4. The drug should be completely dissolved before the solution is withdrawn.

Method of Administration

DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF Pamidria FOR INJECTION USP SHOULD NOT EXCEED 90 MG.

There must be strict adherence to the intravenous administration recommendations for Pamidria for Injection USP in order to decrease the risk of deterioration in renal function.

Hypercalcemia of Malignancy

The daily dose must be administered as an intravenous infusion over at least 2 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, USP, or 5% Dextrose Injection, USP. 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, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period 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, USP, or 5% Dextrose Injection, USP, and administered over a 2-hour period every 3-4 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, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period on a monthly basis.

Pamidria for Injection USP must not be mixed with calcium-containing infusion solutions, such as Ringer’s solution, and should be given in a single intravenous solution and line separate from all other drugs.

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

Pamidria for Injection USP reconstituted with Sterile Water for Injection may be stored under refrigeration at 2°C-8°C (36°F-46°F) for up to 24 hours.

HOW SUPPLIED

Pamidria for Injection USP is available as a white, sterile, lyophilized cake contained in a vial with an externally lacquered, light blue, tear-off, flip-off seal, containing 30 mg Pamidria USP and 470 mg mannitol USP, packaged one vial per carton (NDC No. 59923-601-10).

Pamidria for Injection USP is available as a white, sterile, lyophilized cake contained in a vial with an externally lacquered, white, tear-off, flip-off seal, containing 60 mg Pamidria USP and 400 mg mannitol USP, packaged one vial per carton (NDC No. 59923-602-10).

Pamidria for Injection USP is available as a white, sterile, lyophilized cake contained in a vial with an externally lacquered, dark green, tear-off, flip-off seal, containing 90 mg Pamidria USP and 375 mg mannitol USP, packaged one vial per carton (NDC No. 59923-603-10).

Store at 20° - 25° C (68°-77° F).

Areva

Manufactured for

AREVA Pharmaceuticals, Inc.,

7112 Areva Dr. N.E.

Georgetown, IN 47122

Mfd. by Cipla Ltd. Made in India

© 2011 AREVA Pharmaceuticals, Inc.

Toll-free number: 1-855-853-4760

Revised: July 2015

Pamidria pharmaceutical active ingredients containing related brand and generic drugs:

• Pamidronate Disodium

Pamidria available forms, composition, doses:

• Injectable; Injection; Pamidronate Disodium 30 mg
• Injectable; Injection; Pamidronate Disodium 60 mg
• Injectable; Injection; Pamidronate Disodium 90 mg

Pamidria destination | category:

• Human:
• Agents affecting bone metabolism
• Bisphosphonates
• Cytotoxic chemotherapy

Pamidria Anatomical Therapeutic Chemical codes:

• M05BA03 - Pamidronic Acid

Pamidria pharmaceutical companies:

• Cipla

References

1. Dailymed."PAMIDRONATE DISODIUM (PAMIDRONATE DISODIUM) INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION [AREVA PHARMACEUTICALS INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Depending on the reaction of the Pamidria after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Pamidria not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology