Samarium Sm 153 Lexidronam

Name: Samarium Sm 153 Lexidronam

Warnings

Contraindications

Hypersensitivity to drug, similar phosphate compounds, or components of the formulation

Cautions

May cause myelosuppression; recovery may occur after 8 wks; monitor blood counts for at least 8 wks or until adequate marrow recovery; consider current hematologic status and history of myelosuppressive response to other myelotoxic agents prior to therapy; avoid concurrent chemotherapy and external beam radiation therapy unless benefits outweigh risks, due to potential to additive toxicity

Avoid pregnancy

Thrombocytopenia may be a risk factor in patients with disseminated intravascular coagulation

Transient increase in bone pain may occur within 3 days of administration; may manage with analgesics

Use appropriate precautions in handling and disposal of drug product

Incontinent patients may require urinary catherization to reduce radioactive contamination

Does not prevent spinal cord compression

Incontinent patients may require urinary catherization to reduce risk of radioactive contamination of clothes or bed linens

Patients are at risk for hypocalcemia; whether therapy causes electrocardiographic changes or arrhythmias not studied; caution and appropriate monitoring should be given when administering therapy

Patients urine will be radioactive for several hr, take appropriate precautions

Because concomitant hydration recommended to promote urinary excretion of drug, appropriate monitoring and consideration of additional supportive treatment should be used in patients with a history of congestive heart failure or renal insufficiency

Because approximately one third of drug is excreted in urine, clearance may be reduced in patients with renal impairment not known if dose adjustment needed

Pregnancy & Lactation

Pregnancy Category: D

Lactation: discontinue drug or do not nurse

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Clinical pharmacology

QUADRAMET® (samarium sm 153 lexidronam) (samarium Sm-153 EDTMP) has an affinity for bone and concentrates in areas of bone turnover in association with hydroxyapatite. In clinical studies employing planar imaging techniques, more QUADRAMET® (samarium sm 153 lexidronam) accumulates in osteoblastic lesions than in normal bone with a lesion-to-normal bone ratio of approximately 5. The mechanism of action of QUADRAMET® (samarium sm 153 lexidronam) in relieving the pain of bone metastases is not known.

Distribution: Human protein binding has not been studied; however, in dog, rat and bovine studies, less than 0.5% of samarium-153 EDTMP is bound to protein. At physiologic pH, >90% of the complex is present as 153Sm[EDTMP]-5, and <10% as 153SmH[EDTMP]-4. The octanol/ water partition coefficient is <10-5.

Skeletal Uptake: The greater the number of metastatic lesions, the more skeletal uptake of Sm-153 radioactivity. The relationship between skeletal uptake and the size of the metastatic lesions has not been studied. The total skeletal uptake of radioactivity was 65.5% ± 15.5% of the injected dose in 453 patients with metastatic lesions from a variety o primary malignancies. In a study of 22 patients with a wide range in the number of metastatic sites, the % of the injected dose (% ID) taken up by bone ranged from 56.3% in a patient with 5 metastatic lesions to 76.7% in a patient with 52 metastatic lesions. If the number of metastatic lesions is fixed, over the range 0.1 to 3.0 mCi/kg, the % ID taken up by bone is the same regardless of the dose.

Metabolism: The complex formed by samarium and EDTMP is excreted as an intact, single species that consists of one atom of the Sm-153 and one molecule of the EDTMP, as shown by an analysis of urine samples from patients (n=5) administered samarium Sm-153 EDTMP. Metabolic products of samarium Sm-153 EDTMP were not detected in humans.

Elimination: For QUADRAMET® (samarium sm 153 lexidronam) , calculations of the % ID detected in the whole body, urine and blood were corrected for radionuclide decay. The clearance of activity through the urine is expressed as the cumulated activity excreted. The whole body retention is the simple reciprocal of the cumulated urine activity. (See Skeletal Uptake Section)

Blood: Clearance of radioactivity from the blood demonstrated biexponential kinetics after intravenous injection in 19 patients (10 men, 9 women) with a variety of primary cancers that were metastatic to bone Over the first 30 minutes, the radioactivity (mean ± SD) in the blood decreased to 15% (±8%) of the injected dose with a t 1/2 of 5.5 min (±1.1 min). After 30 minutes, the radioactivity cleared from the blood more slowly with a t1/2 of 65.4 min (± 9.6 min). Less than 1% of the dose injected remained in the blood 5 hr after injection.

Urine: Samarium Sm-153 EDTMP radioactivity was excreted in the urine after intravenous injection. During the first 6 hours, 34.5% (±15.5%) was excreted. Overall, the greater the number of metastatic lesions, the less radioactivity was excreted.

Gender Differences: Gender did not affect the samarium Sm-153 EDTMP blood pharmacokinetics, the cumulative % of radioactivity excreted in urine, or the % radioactivity retained in the skeleton when the number of metastatic lesions is taken into account.

Special Populations

Elderly: The pharmacokinetics of samarium Sm-153 EDTMP did not change with age as seen from comparison of values from people in the age range of 22 to 64 compared to the range 65 to 86 years.

Hepatic Insufficiency: Samarium Sm-153 EDTMP scintiscans in 5 patients with metastatic bone disease did not reveal accumulation of activity in the liver or the intestine; this suggests that hepatobiliary excretion did not occur.

Renal Insufficiency: Patients with renal insufficiency have not been studied.

Drug/Drug Interaction

Drug-drug interaction studies have not been studied.

Pharmacodynamics

The beta particle of 153Sm-EDTMP travels an average of 3.1 mm in soft tissue and 1.7 mm in bone. In clinical trials of 78 patients with metastatic bone lesions who had 13 specific bone scan sites evaluated, the presence or absence of 153Sm-EDTMP uptake is similar to the presence or absence of 99mTc diphosphonate uptake (range 67 to 96% agreemen depending upon the blinded reader and the site of the body). Whether the amount of 153Sm-EDTMP uptake varies with the size of the lesion or to the presence of osteolytic components has not been studied. The clinical benefit of Sm-153-EDTMP in patients with osteolytic lesions is not known. The relationship of different tumor cell types to clinical response has not been studied.

Clinical Trials

Overall QUADRAMET® was evaluated in 580 patients (see ADVERSE EVENTS Section for demographic description). Of these patients, 270 (244 men, 26 women) were studied in two randomized, blinded, placebo controlled clinical trials. These patients had a mean age of 67, and a range 22 to 87 years. Eligible patients had painful metastatic bone lesions that had failed other treatments, had at least a 6 month expected survival and had a positive radionuclide bone scan. Routine x-rays to evaluate the metastatic lesions were not part of the protocol.

In study A, 118 patients were randomized to receive 0.5 mCi/kg QUADRAMET® (samarium sm 153 lexidronam) , 1.0 mCi/kg QUADRAMET® (samarium sm 153 lexidronam) , or a placebo intravenous injection. In study B, 152 patients were randomized to receive either 1.0 mCi/kg QUADRAMET® (samarium sm 153 lexidronam) or a placebo intravenous injection. Both studies were double blind over a 4 week period. Patients scored their daily pain intensity on a visual analogue scale rated from 0 (no or low pain) to 10 (excruciating pain). The area under the pain curve (AUPC) was obtained by integrating the daily pain scores by week. Opioid analgesic use was recorded daily and averaged over each week and expressed in oral morphine milligram equivalents.

Of the 270 patients studied, 232 (86%) had prostate cancer and 38 (14%) had other primary cancers. In study A, 80 (68%) of the patients had prostate cancer and 38 (32%) had a variety of other primary tumors In study B, all (100%) patients had prostate cancer.

The results of the patients' AUPC scores are shown in Table 3. In both trials for each of the 4 weeks of study, the mean AUPC scores decreased in patients who received QUADRAMET® (samarium sm 153 lexidronam) (1.0 mCi/kg). In study A, pain (the AUPC) decrease from baseline was significantly different in QUADRAMET® (samarium sm 153 lexidronam) 1.0 mCi/kg and placebo groups at weeks 3 and 4. In study B, pain (the AUPC) decrease from baseline was significantly different in QUADRAMET® (samarium sm 153 lexidronam) 1.0 mCi/kg and placebo groups at weeks 2, 3 and 4.

Table 3: COMPARISON OF WEEKLY PAIN SCORES (a) AFTER QUADRAMET® (samarium sm 153 lexidronam) 1.0mCi/kg or PLACEBO IV [Intent to Treat]

  STUDY A (n= 73) (b) STUDY B (n= 150) (c)
WEEK Placebo
N=36
1.0 mCi/kg
N=37
Placebo
N=50
1.0 mCi/kg
N=100
Baseline 26.5 (11.8) 28.7 (12.3) 28.5 (14.1) 28.1 (12.9)
1 26.1 (10.3) 27.6 (14.1) 27.9 (14.6) 25.8 (13.1)
2 24.4 (10.4) 23.8 (13.7) 28.1 (15.4) 20.6 (13.9)*
3 24.3 (11.0) 20.5 (11.5)* 25.8 (16.1) 20.1 (13.3)*
4 24.7 (12.1) 18.8 (10.8)* 24.7 (15.3) 19.9 (13.7)*
(a) Area Under the Pain Curve (SD).
(b) Excludes 5 patients with missing baseline or extreme values; and all 40 patients who received 0.5 mCi QUADRAMET® (samarium sm 153 lexidronam) . QUADRAMET® (samarium sm 153 lexidronam) 0.5 mCi/kg can not be distinguished from placebo.
(c) Excludes 2 patients with missing baseline values.
(*) Statistically significant difference in change from baseline in comparison to placebo.

In the two clinical trials, the patient use of analgesics differed. In Study A, the patients did not receive specific instructions on analgesic reduction. In Study B, patients were encouraged to adjust their pain medication as needed. As shown in Table 4, the morphine equivalent analgesic use in study A generally increased from baseline in both the QUADRAMET® (samarium sm 153 lexidronam) and placebo treatment groups; however, the difference between the QUADRAMET® (samarium sm 153 lexidronam) and placebo group change from baseline i not statistically significant. In study B, the placebo treated patients increased their use of opioid analgesics, while the QUADRAMET® (samarium sm 153 lexidronam) treated patients decreased their use of opioid analgesics.

Table 4: COMPARISON OF WEEKLY MEAN ANALGESIC USE (a) BETWEEN QUADRAMET® (samarium sm 153 lexidronam) 1.0 mCi/kg AND PLACEBO GROUPS [Intent to Treat]

  STUDY A (n= 73) (b) STUDY B (n= 150) (c)
WEEK Placebo
N=36
1.0 mCi/kg
N=37
Placebo
N=50
1.0 mCi/kg
N=100
Baseline 93.5 (154.0)(a) 127.1 (189.9) 78.4 (83.1) 96.5 (166.6)
1 106.8 (173.8) 125.7 (192.6) 84.5 (91.1) 93.5 (165.5)
2 127.1 (238.4) 144.8 (276.7) 85.6 (90.9) 82.9 (122.9)
3 133.9 (254.0) 146.6 (278.2) 100.1 (119.4) 79.6 (131.2)*
4 135.6 (222.0) 135.1 (274.0) 106.3 (161.0) 76.8 (132.3)*
(a) Mean Analgesic Use (SD) is in morphine equivalent units; 0 = none.
(b) Excludes 5 patients with missing baseline or with extreme values; and all 40 patients who received 0.5 mCi QUADRAMET® (samarium sm 153 lexidronam) . QUADRAMET® (samarium sm 153 lexidronam) 0.5 mCi/kg can not be distinguished from placebo.
(c) Excludes 2 patients with missing baseline values.
(*) Statistically significant difference in change from baseline in comparison to placebo.

In both studies, the numbers of patients who experienced any decrease in AUPC score without any increase in analgesic use at weeks 3 and 4 were also evaluated. In study A, this occurred in 20/37 (54%) of the patients who received QUADRAMET® (samarium sm 153 lexidronam) 1.0 mCi/kg and 9/36 (25%) of the placebo treated patients. In study B, this occurred in 48/100 (48%) of the QUADRAMET (samarium sm 153 lexidronam) ® treated patients and 11/51 (22%) of the placebo treated patients.

Side effects

Adverse events were evaluated in a total of 580 patients who received QUADRAMET® (samarium sm 153 lexidronam) in clinical trials. Of the 580 patients, there were 472 men and 108 women with a mean age of 66 (range 20 to 87).

Of these patients, 472 (83%) had at least one adverse event. In a subgroup of 399 patients who received QUADRAMET® (samarium sm 153 lexidronam) 1.0 mCi/kg, there were 23 deaths and 46 serious adverse events. The deaths occurred an average of 67 days (9 to 130) after QUADRAMET® (samarium sm 153 lexidronam) . Seriou events occurred an average of 46 days (1 - 118) after QUADRAMET® (samarium sm 153 lexidronam) . Although most of the patient deaths and serious adverse events appear to be related to the underlying disease, the relationship of end stage disease, marrow invasion by cancer cells, previous myelotoxic treatmen and QUADRAMET® (samarium sm 153 lexidronam) toxicity can not be easily distinguished. In clinical studies, two patients with rapidly progressive prostate cancer developed thrombocytopenia and died 4 weeks after receiving QUADRAMET® (samarium sm 153 lexidronam) . One of the patients showed evidence of disseminated intravascular coagulation (DIC); the other patient experienced a fatal cerebrovascular accident, with a suspicion of DIC. The relationship of the DIC to the bone marrow suppressive effect of Samarium is not known. Marrow toxicity occurred in 277 (47%) patients (See WARNINGS section).

In controlled studies, 7% of patients receiving 1.0 mCi/kg QUADRAMET® (samarium sm 153 lexidronam) (as compared to 6% of patients receiving placebo) reported a transient increase in bone pain shortly after injection (flare reaction). This was usually mild, self-limiting, and responded to analgesics.

The most common adverse events observed in controlled clinical studies of QUADRAMET® (samarium sm 153 lexidronam) , are given in Table 6.

TABLE 6: SELECTED ADVERSE EVENTS REPORTED IN GREATER THAN OR EQUAL TO 1.0 % OF PEOPLE WHO RECEIVED QUADRAMET® (samarium sm 153 lexidronam) OR PLACEBO IN CONTROLLED CLINICAL TRIALS

ADVERSE EVENT Placebo QUADRAMET® 1.0 mCi/kg
N = 90 N = 199
# Patients with Any Adverse Event 72 (80%) 169 (85%)
Body As A Whole 56 (62%) 100 (50%)
Pain Flare Reaction 5 (5.6%) 14 (7.0%)
Cardiovascular 19 (21%) 32 (16%)
Arrhythmias 2 (2.2%) 10 (5.0%)
Chest Pain 4 (4.4%) 8 (4.0%)
Hypertension 0 6 (3.0%)
Hypotension 2 (2.2%) 4 (2.0%)
Digestive 44 (49%) 82 (41%)
Abdominal Pain 7 (7.8%) 12 (6.0%)
Diarrhea 3 (3.3%) 12 (6.0%)
Nausea &/or Vomiting 37 (41.1%) 65 (32.7%)
Hematologic & Lymphatic 12 (13%) 54 (27%)
Coagulation Disorder 0 3 (1.5%)
Hemoglobin Decreased 21 (23.3%) 81 (40.7%)
Leukopenia 6 (6.7%) 118(59.3%)
Lymphadenopathy 0 4 (2.0%)
Thrombocytopenia 8 (8.9%) 138(69.3%)
Any Bleeding Manifestations* 8 (8.9%) 32 (16.1%)
Ecchymosis 1 (1.1%) 3 (3.0%)
Epistaxis 1 (1.1%) 4 (2.0%)
Hematuria 3 (3.3%) 10 (5%)
Infection 10 (11.1%) 34 (17.1%)
Fever and/or Chills 10 (11.1%) 17 (8.5%)
Infection, Not Specified 4 (4.4%) 14 (7.0%)
Oral Moniliasis 1 (1.1%) 4 (2.0%)
Pneumonia 1 (1.1%) 3 (1.5%)
Musculoskeletal 28 (31%) 55 (27%)
Myasthenia 8 (8.9%) 13 (6.5%)
Pathologic Fracture 2 (2.2%) 5 (2.5%)
Nervous 39 (43%) 59 (30%)
Dizziness 1 (1.1%) 8 (4.0%)
Paresthesia 7 (7.8%) 4 (2.0%)
Spinal Cord Compression 5 (5.5%) 13 (6.5%)
Cerebrovascular Accident/Stroke 0 2 (1.0%)
Respiratory 24 (27%) 35 (18%)
Bronchitis/Cough Increased 2 (2.2%) 8 (4.0%)
Special Senses 11 (12%) 11 (6%)
Skin & Appendages 17 (19%) 13 (7%)
Purpura 0 2 (1%)
Rash 2 (2.2%) 2 (1%)
*Includes hemorrhage (gastrointestinal, ocular) reported in <1%.

In an additional 200 patients who received QUADRAMET® (samarium sm 153 lexidronam) in uncontrolled clinical trials, adverse events that were reported at a rate of greater than or equal to 1.0% were similar except for 9 (4.5%) patients who had agranulocytosis. Other selected adverse events that were reported in <1% of the patients who received QUADRAMET® (samarium sm 153 lexidronam) 1.0 mCi/kg in any clinical trial include: alopecia, angina, congestive heart failure, sinus bradycardia, and vasodilation.

Read the entire FDA prescribing information for Quadramet (Samarium SM 153 Lexidronam)

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Uses of Samarium Sm 153 Lexidronam

  • It is used to treat bone pain caused by cancer.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
  • Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
  • Feeling very tired or weak.
  • A heartbeat that does not feel normal.
  • A burning, numbness, or tingling feeling that is not normal.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take samarium sm 153 lexidronam or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to samarium sm 153 lexidronam. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Quadramet: 1850 MBq/mL (1 ea, 3 mL [DSC])

Administration

IV: Administer over 1 minute through a secure in-dwelling catheter, followed by a saline flush. Do not dilute or mix with other solutions. Give 500 mL of fluids (IV or orally) prior to administration. To minimize bladder exposure, patients should void as soon as possible after injection. Precautions should be taken for 12 hours following administration. If possible, patients should urinate in a toilet (rather than a urinal); flush the toilet several times after each use. Promptly clean any spilled urine; if blood or urine is on clothing, wash separately or store for 1 to 2 weeks to allow for radioactive decay.

Radiopharmaceutical; use appropriate precautions for handling and disposal.

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