Professional Drug Information > Quadramet

Samarium Sm 153 Lexidronam (Systemic)

VA CLASSIFICATION
Primary: AN600

Commonly used brand name(s): Quadramet.

A commonly used name for samarium Sm 153 lexidronam is Sm 153 ethylenediaminetetramethylene phosphonic acid or Sm 153-EDTMP.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antineoplastic—

Indications

Accepted

Pain, metastatic bone lesion–associated (treatment)—Samarium Sm 153 lexidronam (Sm 153-EDTMP) is indicated in the palliative treatment of bone pain in patients with confirmed osteoblastic metastatic bone lesions that exhibit increased radiopharmaceutical uptake on bone scintigraphy ^{{01} {03} {04} {05} {09} {10}}.


Physical Properties

Nuclear Data ^{01}

Radionuclide (half-life)	Mode of decay	Principal photon emissions (keV)*	Mean number of emissions/ disintegration
Sm 153 (46.3 hrs)	Beta	Beta (640) Beta (710) Beta (810) Gamma (103)	0.30 0.50 0.20 0.29

^* Maximum energies for beta emissions are listed. The average beta particle energy is 233 keV ^{{01} {09}}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Sm 153: Neutron irradiation of isotopically enriched Sm 152 oxide ^{{01} {09}}.
Molecular weight—
    696.01 (pentasodium form) ^{02}

Mechanism of action/Effect:

Pain of metastatic bone lesions—The exact mechanism of action of Sm 153-EDTMP in relieving the pain of bone metastases is not known ^{01}. When samarium Sm 153 is chelated to ethylenediaminetetramethylene phosphonic acid (EDTMP), a bone-seeking diphosphonate complex is produced that concentrates in areas of bone turnover in association with hydroxyapatite crystals ^{{01} {07}}. The lesion-to-normal-bone accumulation ratio is approximately 5 ^{{01} {03}}. The turnover rate of Sm 153-EDTMP in the tumor is slow enough to allow samarium Sm 153 to deliver a sufficient radiation dose to produce a palliative effect ^{03}. Due to the short range of the beta particles, the cells close to regions containing Sm 153-EDTMP will be preferentially irradiated ^{05}.

Distribution:

Sm 153-EDTMP is cleared from the blood rapidly after intravenous administration ^{{01} {03}}. The radioactivity in the blood decreases to approximately 15% (mean) of the administered activity over the first 30 minutes, and less than 1% of the administered activity remains in the circulation at 5 hours postinjection ^{{01} {03}}. The extent of total bone uptake of Sm 153-EDTMP is dependent on the number and activity of metastatic bone lesions ^{{01} {09}}. In a group of patients with metastatic lesions from a variety of primary malignancies, the total skeletal uptake of radioactivity was found to be 65.5 ± 15.5% of the injected dose ^{01}. No local accumulation of Sm 153-EDTMP has been detected outside the skeleton, with the exception of the excretory organs (i.e., kidney, bladder) ^{{03} {06} {09}}.

Protein binding:

Human protein binding of Sm 153-EDTMP has not been studied ^{01}. In dog, rat, and bovine studies, less than 0.5% of Sm 153-EDTMP was bound to protein ^{01}.

Biotransformation:

Sm 153-EDTMP undergoes no biotransformation ^{01}.

Half-life:

Elimination (from blood)—Within the first 30 minutes of Sm 153-EDTMP administration: Approximately 5.5 minutes ^{01}.

30 minutes after administration: Approximately 65.4 minutes ^{01}.

Onset of action:

In some studies, pain relief occurred in patients as early as 1 to 2 weeks after administration of Sm 153-EDTMP, with maximum relief obtained by 4 to 6 weeks ^{{03} {04} {05} {09}}.

Duration of action:

Duration of pain relief has varied from 2 to 35 weeks ^{{03} {04} {05} {10} {11}}.

Radiation dosimetry:
^{01}{07}

Estimated absorbed radiation dose*
Organ	mGy/MBq	rad/mCi
Bone surfaces	6.76	25
Red marrow	1.54	5.7
Urinary bladder wall	0.097	3.6
Kidneys	0.018	0.065
Large intestine, lower	0.01	0.037
Ovaries	0.0086	0.032
Muscle	0.0076	0.028
Small intestine	0.0062	0.023
Large intestine, upper	0.0054	0.02
Testes	0.0054	0.02
Liver	0.0051	0.019
Spleen	0.0049	0.018
Stomach	0.0041	0.015
Whole body	0.011	0.040

^* For adults (weighing 70 kg); intravenous injection. Data based on bladder voiding every 4.8 hours ^{{01} {09}}.

Elimination:
    Renal (34.5 ± 15.5% of the administered activity is excreted within 6 hours) ^{{01} {04}}. In general, the greater the number of metastatic lesions, the less radioactivity is excreted ^{{01} {04}}.


Precautions to Consider

Carcinogenicity

Osteosarcomas occurred in a 2-year toxicity/carcinogenicity study in male and female rats given EDTMP by gastric intubation in daily doses of 50 mg and 150 mg per kg of body weight, respectively ^{01}.

Mutagenicity

Negative results were observed (with nonradioactive samarium-EDTMP) in the Salmonella reverse mutation (Ames) test, unscheduled DNA synthesis in rat liver primary cell culture, chromosomal aberration assay in rat lymphocytes, CHO/HGPRT forward mutation assay, and mouse bone marrow micronucleus test ^{01}.

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies with Sm 153-EDTMP have not been done in humans ^{01}. Radiopharmaceuticals generally are not recommended for therapeutic use during pregnancy because of the risk to the fetus from radiation exposure. Sm 153-EDTMP would be expected to cause adverse effects, such as bone marrow toxicity, in the fetus.

To avoid the possibility of fetal exposure to radiation, in those circumstances in which the patient's pregnancy status is uncertain, a pregnancy test will help to prevent inadvertent administration of this preparation during pregnancy ^{01}.

Studies have not been done in animals ^{01}.

FDA Pregnancy Category D ^{01}.

Breast-feeding

It is not known whether Sm 153-EDTMP is distributed into breast milk ^{01}. Because of the potential risk to the infant from radiation exposure, breast-feeding should be completely discontinued and formula feedings used instead after administration of Sm 153-EDTMP ^{{01} {09}}.

Pediatrics

Appropriate studies on the relationship of age to the effects of Sm 153-EDTMP have not been performed in children up to 16 years of age ^{01}. Safety and efficacy have not been established ^{01}.


Geriatrics


Appropriate studies on the relationship of age to the effects of Sm 153-EDTMP have not been performed in the geriatric population. However, clinical trials and studies that included older patients were conducted, and geriatrics-specific problems that would limit the usefulness of Sm 153-EDTMP in the elderly are not expected ^{{01} {03} {05}}.


Dental

The bone marrow depressant effects of Sm 153-EDTMP may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks ^{09}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Bone marrow depressants, other (see Appendix II )    (additive bone marrow depression may occur; Sm 153-EDTMP should not be administered concurrently with chemotherapy or external beam radiation unless the benefits outweigh the risks; also, Sm 153-EDTMP should not be administered after either of these treatments until adequate recovery of bone marrow function ^{01})


Etidronate^{09}    (etidronate may interfere with bone uptake of Sm 153-EDTMP; etidronate should be discontinued at least 2 weeks before therapy with Sm 153-EDTMP ^{{09} {12} {13} {14}})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Serum tumor markers, such as prostate-specific antigen (PSA) and prostate acid phosphatase (PAP)^{05}    (concentrations may be decreased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Previous allergic reaction to EDTMP or similar phosphonate compounds^{01}
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression^{01}    (increased risk of toxicity due to compromised bone marrow function)


Renal function impairment^{09}{14}    (increased risk of radiation to nontarget organs due to poor urinary excretion)


Spinal cord compression, suspected^{01}{09}    (frequently occurs in patients with known metastases to the cervical, thoracic, or lumbar spine; Sm 153-EDTMP is not indicated for treatment of spinal cord compression, thus to avoid permanent disability, appropriate diagnostic and therapeutic measures must be taken ^{{01} {09}})


Urinary incontinence^{01}    (increased risk of radiation contamination of environment; therefore, urinary catheterization is recommended)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Blood studies, including hemoglobin determinations and leukocyte and platelet counts    (recommended prior to therapy and weekly beginning 2 weeks after initiation of therapy and continued for at least 8 weeks, or until recovery of adequate bone marrow function ^{{01} {04}})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Bone marrow depression leading to thrombocytopenia^{{01} {04}{05}} (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)
    
and leukopenia^{01}{04}{05} (cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination)

Note: In clinical trials, white blood cell counts and platelet counts decreased to a nadir (approximately 40 to 50% of baseline) in 95% of patients within 3 to 5 weeks after Sm 153-EDTMP administration and usually returned to pretreatment levels by 8 weeks ^{01}.


Incidence less frequent
    
Cardiac arrhythmias^{01} (irregular heartbeat)




Those indicating need for medical attention only if they continue or are bothersome
    
Flare reaction ^{03}{04}{05} (increase in bone pain, transient)
    
nausea and vomiting^{01}

Note: The flare reaction usually occurs within 72 hours of injection ^{01}.





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Samarium Sm 153 Lexidronam (Therapeutic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Description of use
Action in the body: Accumulation of radioactivity in bone, especially adjacent to areas of tumor involvement; localized radiation exposure to these sites provides reduction in bone pain ^{09}

Before using this medication
»   Conditions affecting use, especially:
Previous allergic reaction to the radiopharmaceutical preparation or similar phosphonate compounds

Pregnancy—Use not recommended; risk to fetus from radiation exposure





Breast-feeding—Cessation of nursing is recommended to avoid any unnecessary absorbed radiation dose to the infant ^{09}
Other medications, especially bone marrow depressants
Other medical problems, especially bone marrow depression

Proper use of this medication
Special preparatory instructions may apply; patient should inquire in advance

Ingesting 500 mL of fluids prior to injection, unless cardiac status indicates otherwise, and voiding frequently afterwards to minimize radiation dose to bladder ^{09}

Notifying physician prior to administration if having an incontinence problem; catheterization may be required to prevent radiation contamination

Precautions after using this medicine
» Importance of close monitoring by the physician
»
Preventing radiation contamination of other persons or environment
For the first 12 hours ^{01}—

• Using a normal toilet instead of a urinal


• Double-flushing toilet


• Wiping any spilled urine with a tissue and flushing it away


• Washing hands after using or cleaning toilet


• Immediately laundering clothes and linens soiled with urine or blood; washing them separately from other clothes


• Washing away any spilled blood

»
Caution if significant bone marrow depression occurs
Abnormally low white blood cell counts—

• Avoiding exposure to persons with bacterial infections, especially during periods of low blood counts; checking with physician immediately if cough or hoarseness, fever or chills, lower back or side pain, or painful or difficult urination occurs


• Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done


• Not touching eyes or inside of nose unless hands washed immediately before


Abnormally low platelet counts—

• Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur


• Using caution to avoid accidental cuts with use of sharp objects such as a safety razor or fingernail or toenail cutters


• Avoiding situations where bruising or injury could occur



Side/adverse effects
Signs of potential side effects, especially bone marrow depression and cardiac arrhythmias


General Dosing Information
Radiopharmaceuticals are to be administered only by or under the supervision of physicians who have had extensive training in the safe use and handling of radioactive materials and who are licensed by the Nuclear Regulatory Commission (NRC) or the appropriate Agreement State agency, if required, or, outside the U.S., the appropriate authority ^{01}.

There must be a histological diagnosis of malignancy, and the presence of bone metastases must be confirmed (e.g., by skeletal imaging with technetium Tc 99m–labeled phosphate or phosphonate radiopharmaceutical) prior to therapy with Sm 153-EDTMP ^{{01} {05} {09}}.

Unless cardiac status indicates otherwise, the patient should ingest at least 500 mL of fluids prior to injection and void frequently following the administration of Sm 153-EDTMP, to minimize radiation dose to the bladder ^{{01} {09}}.

A properly functioning intravenous line must be secured to prevent extravasation of Sm 153-EDTMP. Extravasation may cause a very high local radiation dose, which may result in tissue injury or necrosis ^{{09} {14}}.

Safety considerations for handling this radiopharmaceutical
Guidelines for the receipt, storage, handling, dispensing, and disposal of radioactive materials are available from scientific, professional, state, federal, and international bodies. Handling of this radiopharmaceutical should be limited to those individuals who are appropriately qualified and authorized ^{08}.


Parenteral Dosage Forms

SAMARIUM Sm 153 LEXIDRONAM INJECTION

Usual adult and adolescent administered activity
Pain of metastatic bone lesions
Intravenous, 37 megabecquerels (1 millicurie) per kg of body weight given over a period of one minute ^{{01} {06} {09} {11}}.


Note: A saline flush is recommended after injection of Sm 153-EDTMP ^{01}.


Usual pediatric administered activity
Children up to 16 years of age
Safety and efficacy have not been established ^{01}.


Usual geriatric administered activity
See Usual adult and adolescent administered activity.

Strength(s) usually available
U.S.—


35 mg of EDTMP, 5.3 mg of calcium as Ca(OH)2, 14.1 mg of sodium as NaOH, equivalent to 44 mg Ca/Na EDTMP (anhydrous calcium), 5 to 46 micrograms of samarium (specific activity of approximately 37 to 407 megabecquerels [1 to 11 millicuries] per microgram of samarium), and 1850 ± 185 megabecquerels (50 ± 5 millicuries) of samarium Sm 153, per mL at time of calibration (Rx) [Quadramet]^{01}

Note: This product is supplied in a 10-mL single-dose vial.


Canada—
Not commercially available.

Packaging and storage:
Store between -20 and -10 ºC (-4 and 14 ºF), unless otherwise specified by manufacturer. Store in a lead-shielded container. ^{01}

Stability:
Sm 153-EDTMP injection expires 48 hours after the time of calibration noted on the label, or 8 hours after thawing, whichever is earlier ^{01}. Sm 153-EDTMP injection contains no antibacterial preservative ^{{01} {09}}.

Incompatibilities:
Sm 153-EDTMP contains calcium and may be incompatible with solutions containing molecules that can complex with and form calcium precipitates ^{01}.


Caution:
Radioactive material.

Developed: 12/03/1998

References

1. Quadramet package insert (DuPont—US), New 2/97.
   

2. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 654.
   

3. Ahonen A, Joensuu H, Hiltunen J, et al. Samarium-153-EDTMP in bone metastases. J Nucl Biol Med 1994 Dec; 38(4 Suppl 1): 123-7.
   

4. Turner JH, Martindale AA, Sorby P, et al. Samarium-153-EDTMP therapy of disseminated skeletal metastasis. Eur J Nucl Med 1989; 15(12): 784-95.
   

5. Collins C, Eary JF, Donaldson G, et al. Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial. J Nucl Med 1993 Nov; 34(11): 1839-44.
   

6. Bayouth JE, Macey DJ, Kasi LP, et al. Dosimetry and toxicity of samarium-153-EDTMP administered for bone pain due to skeletal metastases. J Nucl Med 1994 Jan; 35(1): 63-9.
   

7. Eary JF, Collins C, Stabin M, et al. Samarium-153-EDTMP biodistribution and dosimetry estimation. J Nucl Med 1993 Jul; 34(7): 1031-6.
   

8. Radiopharmaceuticals Advisory Panel Meeting, 4/96.
   

9. Reviewers' comments as of monograph revision of 1/98.
   

10. Robinson RG, Preston DF, Schiefelbein M, et al. Strontium 89 therapy for the palliation of pain due to osseus metastases. JAMA 1995 Aug 2; 274(5): 420-4.
    

11. Albert AS, Smit BJ, Loww WK, et al. Dose response relationship and multiple dose efficacy and toxicity of samarium-153-EDTMP in metastatic cancer to bone. Radiother Oncol 1997 May; 43(2): 175-9.
    

12. Murphy KJ, Line BR, Malfetano J. Etidronate therapy decreases the sensitivity of bone scanning with methylene diphosphonate labelled with technetium-99m. Can Assoc Radiol J 1997 Jun; 48(3): 199-202.
    

13. Krasnow AZ, Collier BD, Isitman AT, et al. False-negative bone imaging due to etidronate disodium therapy. Clin Nucl Med 1988 Apr; 13(4): 264-7.
    

14. Reviewers' comments to ballot of 4/98.
    

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