Amsacrine (Systemic)



USAN:
Amsacrine
VA CLASSIFICATION
Primary: AN900

Commonly used brand name(s): AMSA P-D.

Other commonly used names are
acridinyl anisidide and m-AMSA.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.



Category:


Antineoplastic—

Indications

Accepted

Leukemia, acute, adult (treatment)— Amsacrine is indicated for induction of remission in acute adult leukemia refractory to conventional therapy.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    393.46{01}

Mechanism of action/Effect:

Amsacrine binds to DNA through intercalation and external binding and has base specificity for A-T pairs.{01} Cycling cells are two to four times more sensitive to amsacrine than are resting cells. Cells initially in S and G2 phases are grossly delayed in their capacity for normal progression, leading to an accumulation of cells in the S phase, followed at later times by arrest in the G2 phase.{01}

Distribution:

Volume of distribution (Vol D)—1.67 L/kg{02}. Amsacrine does not significantly penetrate into the CNS{04}.

Protein binding:

Very high (96% to 98%){02}{03}

Biotransformation:

Hepatic; extensive (inactive metabolites).{04}

Half-life:


Distribution:

10 to 15 minutes following a 90 mg/m 2 dose over 60 minutes{01}.



Elimination:

8 to 9 hours following a 90 mg/m 2 dose over 60 minutes{01}.


Peak plasma concentration

Concentrations are dose-dependent, increasing from 0.47 to 12.3 micromole as the dose is escalated from 10 to 90 mg/m 2.{01}

Duration of action:

Remissions induced by amsacrine are brief and variable if not followed by consolidation or maintenance regimens.{01}

Elimination:
    Renal—35% of the dose is excreted by the kidneys within 72 hours after administration (20% as intact drug).{01}
    Biliary—Amsacrine is also eliminated by biliary excretion{01}


Precautions to Consider

Pregnancy/Reproduction
Fertility—
No studies have been performed in animals. There is no evidence as to whether this drug may adversely affect fertility in either men or women.{01}

Pregnancy—
Safe use of amsacrine in pregnancy has not been established.{01} Studies have not been done in humans.

It usually is recommended that use of antineoplastics, especially combination chemotherapy, be avoided during pregnancy whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.{05}

Other hazards to the fetus include adverse reactions seen in adults.{05}

In general, use of contraception is recommended during cytotoxic drug therapy.{05}

Studies have not been done in animals.{01}

Breast-feeding

Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended during chemotherapy because of the potential risks to the infant (adverse effects, mutagenicity, carcinogenicity).{05}

Pediatrics

No information is available on the relationship of age to the effects of amsacrine in pediatric patients. Safety and efficacy have not been established.


Geriatrics


No information is available on the relationship of age to the effects of amsacrine in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require adjustment of dosage in patients receiving amsacrine.


Dental

The bone marrow depressant effects of amsacrine 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, including caution in use of regular toothbrushes, dental floss, and toothpicks.

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):

» Blood dyscrasia-causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of amsacrine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of amsacrine, if necessary, should be based on blood counts )


» Bone marrow depressants, other (see Appendix II) or
» Radiation therapy    (additive bone marrow depression, including severe dermatitis and/or mucositis, may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by amsacrine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by amsacrine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the amsacrine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



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
Uric acid concentrations in blood    (may be increased{01})


Hematocrit/hemoglobin values and
Leukocyte count and
Platelet count    (may be decreased; leukocyte counts as low as 1000 cells per cubic millimeter can be expected during amsacrine therapy{01})


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).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression    (will be increased; prolonged bone marrow aplasia may occur; leukopenia is usually transient, reaching its nadir at 11 to 13 days after treatment, with recovery usually occurring by the 17th to 25th day{01})


» Cardiac arrhythmias    (cases of acute arrhythmias have been reported during or immediately after amsacrine infusion{01})


» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe, generalized disease)


» Hepatic function impairment    (dose reduction is recommended in patients with significant hepatic dysfunction [bilirubin > 2 mg%]{01})


» Infection, pre-existing    (recovery may be impaired)


» Renal function impairment    (dose reduction is recommended in cases of significant renal impairment [BUN > 20 mg%, creatinine > 1.2 mg%]{01})


Note: Caution also should be used in patients who have had previous cytotoxic drug therapy or radiation therapy.



Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Hepatic function{01}    (recommended prior to initiation of therapy and at periodic intervals during treatment; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


» Renal function{01}    (recommended prior to initiation of therapy and at periodic intervals during treatment; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


» Electrocardiogram (ECG) studies    (recommended prior to initiation of therapy and at periodic intervals during and after treatment{01})


» Hematocrit or hemoglobin and
» Leukocyte count, total and differential and
» Platelet count    (determinations recommended prior to each course of amsacrine therapy; delay, omission, and/or reduction of subsequent doses by 20% is recommended, especially if life-threatening infection or hemorrhage during the preceding course occurred{01})


Uric acid concentrations, serum{01}    (recommended prior to initiation of therapy and at periodic intervals during treatment; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)




Side/Adverse Effects

Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.

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
    
Anemia (unusual tiredness or weakness)
    
leukopenia (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination )
    
mucositis or stomatitis (sores, ulcers, or white spots on lips, tongue, or inside mouth)—reported at higher doses for mucositis
    
perirectal abscess (accumulation of pus or swollen, red, tender area of infection around the rectum)
    
thrombocytopenia (black tarry stools; blood in urine or stools ; pinpoint red spots on skin; unusual bleeding or bruising)
{01}
Note: With leukopenia, the nadir of leukocyte count occurs 11 to 13 days after a dose. Recovery usually occurs within 25 days after a dose.{01}


Incidence less frequent or rare
    
Hematemesis (vomiting of blood or material that looks like coffee grounds)
    
hepatotoxicity (abdominal pain or tenderness; dark urine; itching; yellow eyes or skin)— usually transient
    
hypotension ( blurred vision; confusion; dizziness, faintness, or light-headedness )
    
jaundice ( yellow eyes or skin)
    
pancytopenia ( diarrhea; fever; nausea; vomiting)—reported with prolonged therapy
    
seizure
    
tachycardia ( fast, pounding, or irregular heartbeat or pulse; palpitations )
    
ventricular arrhythmia (rapid or irregular heartbeat)

{01}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain
    
confusion
    
dizziness
    
diarrhea
    
headache
    
nausea or vomiting
    
paresthesias (burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings)
{01}


Incidence less frequent or rare
    
Anorexia (loss of appetite)
    
asthenia (loss of strength or energy; weakness)
    
dysphasia (difficulty swallowing)
    
gingivitis (bleeding gums; redness and swelling of gums)
    
gum hemorrhage ( bleeding gums)
    
lethargy ( unusual tiredness or weakness)
    
musculoskeletal pain (muscle or bone pain)
    
phlebitis (pain or redness at site of injection)
    
rash, purpuric or maculopapular
    
urticaria ( hives or itching)
{01}

Those not indicating need for medical attention
Incidence less frequent or rare
    
Alopecia (loss of hair)
{01}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Treatment of overdose
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Amsacrine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:

Pregnancy—Use is not recommended because of embryotoxic, fetotoxic, and carcinogenic potential; advisability of using contraception; informing physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of potential serious adverse effects
Other medications, especially blood dyscrasia–causing medications, bone marrow depressants, live virus vaccines, previous cytotoxic drug or radiation therapy
Other medical problems, especially bone marrow depression, cardiac arrhythmias, existing or recent chickenpox or herpes zoster infection, hepatic function impairment, preexisting infection, renal function impairment

Proper use of this medication

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by the physician, especially blood counts, cardiac rhythm, liver function tests, and renal function tests

Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine, or wearing a protective mask that covers nose and mouth

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

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

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

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

Avoiding contact sports or other situations where bruising or injury could occur
» Possibility of local tissue injury and scarring if infiltration of intravenous solution occurs; telling doctor or nurse right away about redness, pain, or swelling at injection site


Side/adverse effects
Signs of potential side effects, especially anemia, leukopenia, mucositis or stomatitis, perirectal abscess, thrombocytopenia, hematemesis, hepatotoxicity, hypotension, jaundice, pancytopenia, seizure, tachycardia, and ventricular arrhythmia


General Dosing Information
Amsacrine is administered by intravenous infusion. {01}

Amsacrine should be administered only under the supervision of a physician experienced in cancer chemotherapy.{01} Adequate facilities should be available for the management of complications of bone marrow suppression.{01}

Amsacrine injection must be diluted prior to use.{01}

Phlebitis, related to the concentration of amsacrine administered, may be reduced by infusing the diluted drug over a period of 60 to 120 minutes.{01}

Care must be taken to avoid extravasation during intravenous administration because of the risk of severe irritation or necrosis.{01}

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of amsacrine. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in the use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastic agents may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves , goggles, gowns, and masks.
   • Pregnant personnel should not come in contact with antineoplastic medication containers or mixing supplies.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampules, and unused medication.
   • Use of proper technique in handling spills, including the use of dilute sodium hypochlorite solution ( 5% {01} active chlorine) and water, and proper disposal of waste.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.

If amsacrine comes into contact with the skin or mucosa, immediately wash thoroughly with soap and water.{01}


Parenteral Dosage Forms

AMSACRINE INJECTION

Usual Adult Dose
Leukemia, acute, adult (treatment)
Induction: Intravenous infusion (over 60 to 120 minutes), 75, 100, or 125 milligrams per square meter of body surface area per day, given on Days 1 through 5, repeated at three-to-four-week intervals. Two courses may be necessary to achieve induction.{01}

Maintenance: Once remission has been obtained, the maintenance dose should be approximately one half that of the induction dose, repeated every four to eight weeks depending upon the peripheral blood counts and bone marrow recovery from myelosuppression.{01}

Note: The dose of amsacrine should be increased by 20% for the second and each subsequent course if the patient has had no significant toxicity in the previous course, and if marrow hypoplasia has not been achieved. If patients have had life-threatening infection or hemorrhage during the previous course, consider decreasing the dose by 20%. Second and subsequent courses should not be initiated until recovery from drug-induced myelosuppression or evidence of residual leukemic infiltrate is evident.{01}
Dose reduction is recommended in patients with significant hepatic impairment (bilirubin > 2 mg%).{01}
Dose reduction is recommended in patients with significant renal impairment (BUN > 20 mg%, creatinine > 1.2 mg%).{01}



Usual Pediatric Dose
Safety and efficacy have not been established.

Strength(s) usually available
U.S.—
Not commercially available.

Canada—


50 mg per mL (1.5–mL single-dose ampoules) (Rx) [AMSA P-D (N, N-dimethylacetamide)]{01}

Note: Product is packaged together with accompanying diluent (13.5 mL). The diluent contains L-lactic acid (0.035 M).{01}


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F) unless otherwise specified by manufacturer.

Preparation of dosage form:
Amsacrine injection must be diluted, using the following procedure—


To prepare stock solution:
Aseptically transfer 1.5 mL from the ampoule to the vial which contains 13.5 mL of L-lactic acid diluent. Use only the diluent provided. The resulting orange-red solution is the stock solution which contains 5 mg amsacrine per mL. It is preferable to use glass syringes for step one, however, plastic syringes can be used, provided that amsacrine remains in the syringe for no longer than 15 minutes.{01}



To prepare the infusion:
Prepare the intravenous infusion solution by aseptically transferring the total daily dose of stock solution to 500 mL Dextrose Injection USP.{01}


Stability:
The stock solution is chemically stable for 24 hours at room temperature when protected from exposure to direct sunlight. Since this solution does not contain a preservative, unused portions should be discarded.{01}

The freshly prepared intravenous infusion is chemically stable for up to 7 days when using an Abbott plastic container or glass bottle. However, the solution should be used within 24 hours when stored at room temperature or 72 hours when refrigerated.{01}

Incompatibilities:
Amsacrine should not be mixed with saline solutions. Amsacrine is incompatible with solutions containing chloride ions.{01}

Auxiliary labeling:
   • Must be diluted prior to administration.



Developed: 04/24/2000



References
  1. Product Information: Amsa P-D, amsacrine. Parke-Davis Canada, Scarborough, Ontario (PI revised 7/1984) reviewed 4/2000.
  1. Jurlina JL, Varcoe AR & Paxton JW: Pharmacokinetics of amsacrine in patients receiving combined chemotherapy for treatment of acute myelogenous leukemia. Cancer Chemother Pharmacol 1985; 14:21-25.
  1. Paxton JW, Jurlina JL & Foote SE: The binding of amsacrine to human plasma proteins. J Pharm Pharmacol 1986; 38:432–438.
  1. Hall SW, Freidman J, Benjamin RS et al: Human pharmacokinetics of a new acridine derivative, 4'-(9-acridinylamino)-methanesulfon-m-anisidide (NSC 249992). Cancer Res 1983; 43:3422–3426.
  1. Standard statement/precaution approved by Panel consensus for all antineoplastics monographs.
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