DESCRIPTION
id: 6de211be-1f9e-4520-b9ad-7ceaedfb108f
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3
Allopurinol sodium for injection is a xanthine oxidase inhibitor. It is available in vials as the sterile lyophilized sodium salt of allopurinol sodium equivalent to 500 mg of allopurinol. Allopurinol sodium for injection contains no preservatives.
The chemical name for allopurinol sodium is 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one monosodium salt. It is a white amorphous mass with a molecular weight of 158.09 and molecular formula C5H3N4NaO. The structural formula is
The pKa of allopurinol sodium is 9.31.
CLINICAL PHARMACOLOGY
id: d8c02c83-939f-4431-a2af-b66004f4c68b
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1
Allopurinol acts on purine catabolism without disrupting the biosynthesis of purines. It reduces the production of uric acid by inhibiting the biochemical reactions immediately preceding its formation. The degree of this decrease is dose dependent.
Allopurinol is a structural analogue of the natural purine base, hypoxanthine. It is an inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism in man. Allopurinol is metabolized to the corresponding xanthine analogue, oxypurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.
Reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is markedly enhanced when their oxidations are inhibited by allopurinol and oxypurinol. This reutilization does not disrupt normal nucleic acid anabolism, however, because feedback inhibition is an integral part of purine biosynthesis. As a result of xanthine oxidase inhibition, the serum concentration of hypoxanthine plus xanthine in patients receiving allopurinol for treatment of hyperuricemia is usually in the range of 0.3 to 0.4 mg/dL compared to a normal level of approximately 0.15 mg/dL. A maximum of 0.9 mg/dL of these oxypurines has been reported when the serum urate was lowered to less than 2 mg/dL by high doses of allopurinol. These values are far below the saturation levels, at which point their precipitation would be expected to occur (above 7 mg/dL).
The renal clearance of hypoxanthine and xanthine is at least 10 times greater than that of uric acid. The increased xanthine and hypoxanthine in the urine have not been accompanied by problems of nephrolithiasis. There are isolated case reports of xanthine crystalluria in patients who were treated with oral allopurinol.
The action of oral allopurinol differs from that of uricosuric agents, which lower the serum uric acid level by increasing urinary excretion of uric acid. Allopurinol reduces both the serum and urinary uric acid levels by inhibiting the formation of uric acid. The use of allopurinol to block the formation of urates avoids the hazard of increased renal excretion of uric acid posed by uricosuric drugs.
PHARMACOKINETICS
id: db655c35-6d6d-4f19-8124-f5dd02e6c0df
displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5
Following intravenous administration in six healthy male and female subjects, allopurinol was rapidly eliminated from the systemic circulation primarily via oxidative metabolism to oxypurinol, with no detectable plasma concentration of allopurinol after 5 hours post dosing. Approximately 12% of the allopurinol intravenous dose was excreted unchanged, 76% excreted as oxypurinol, and the remaining dose excreted as riboside conjugates in the urine. The rapid conversion of allopurinol to oxypurinol was not significantly different after repeated allopurinol dosing. Oxypurinol was present in systemic circulation in much higher concentrations and for a much longer period than allopurinol; thus, it is generally believed that the pharmacological action of allopurinol is mediated via oxypurinol. Oxypurinol was primarily eliminated unchanged in urine by glomerular filtration and tubular reabsorption, with a net renal clearance of about 30 mL/min.
To compare the pharmacokinetics of allopurinol and oxypurinol between intravenous (i.v.) and oral (p.o.) administration of allopurinol sodium for injection, a welI-controlled, four-way crossover study was conducted in 16 male healthy volunteers. Allopurinol sodium for injection was administered via an intravenous infusion over 30 minutes. Pharmacokinetic parameter estimates of allopurinol (mean ± S.D.) following single i.v. and p.o. administration of allopurinol sodium for injection are summarized as follows:
Administration of Allopurinol Sodium for Injection
|
Allopurinol Parameters
|
100 mg i.v.
|
300 mg i.v.
|
100 mg p.o.*
|
300 mg p.o.
|
|
Cmax (mcg/mL)
|
1.58 ± 0.22
|
5.12 ± 0.82
|
0.53 ± 0.1
|
1.35 ± 0.49
|
|
Tmax (hr)
|
0.5
|
0.5
|
1 ± 0.39
|
1.67 ± 0.96
|
|
T ½ (hr)
|
1 ± 0.46
|
1.21 ± 0.33
|
0.98 ± 0.43
|
1.32 ± 0.32
|
AUC0
– >∞ (hr•mcg/mL)
|
1.99 ± 0.63
|
7.1 ± 1.28
|
1.03 ± 0.24
|
3.69 ± 0.96
|
|
CL (mL/min/kg)
|
12.2 ± 3.11
|
9.94 ± 2.36
|
|
|
|
Vss (L/kg)†
|
0.84 ± 0.13
|
0.87 ± 0.13
|
|
|
|
Fabsolute (%)††
|
|
|
48.8 ± 19.7
|
52.7 ± 13.1
|
* n=7
† Volume of Distribution (Steady-State)
††Absolute Bioavailability
Oxypurinol was measurable in the plasma within 10 to 15 minutes following the administration of allopurinol sodium for injection. Pharmacokinetic parameter estimates of oxypurinol following i.v. and p.o. administration of allopurinol sodium for injection are shown below:
Administration of Allopurinol Sodium for Injection
|
Oxypurinol Parameters
|
100 mg i.v.
|
300 mg i.v.
|
100 mg p.o.
|
300 mg p.o.
|
|
Cmax (mcg/Ml)
|
2.2 ± 0.31
|
6.18 ± 0.78
|
2.36 ± 0.3
|
6.36 ± 0.83
|
|
Tmax (hr)
|
3.89 ± 1.41
|
4.16 ± 1.2
|
3.1 ± 1.49
|
4.13 ± 1.35
|
|
T ½ (hr)
|
24.1 ± 5.4
|
23.5 ± 4.5
|
24.9 ± 8.4
|
23.7 ± 3.4
|
|
AUC0 – >∞ (hr•mcg/mL)
|
80 ± 24
|
231 ± 54
|
83 ± 22
|
245 ± 49
|
|
Frelative (%)*
|
|
|
107 ± 25
|
108 ± 9
|
* Relative Bioavailability
In general, the ratio of the area under the plasma concentration vs time curve (AUC0 – >∞) between oxypurinol and allopurinol was in the magnitude of 30 to 40. The Cmax and AUC0 – >∞, for both allopurinol and oxypurinol following i.v. administration of allopurinol sodium for injection were dose proportional in the dose range of 100 to 300 mg. The half-life of allopurinol and oxypurinol was not influenced by the route of allopurinol sodium for injection administration. Oral and intravenous administration of allopurinol sodium for injection at equal doses produced nearly superimposable oxypurinol plasma concentration vs time profiles, and the relative bioavailability of oxypurinol (Frelative) was approximately 100%. Thus, the pharmacokinetics and plasma profiles of oxypurinol, the major pharmacological component derived from allopurinol, are similar after intravenous and oral administration of allopurinol sodium for injection.
INDICATIONS AND USAGE
id: e955a05d-7b2d-456c-8b2f-7b3acfbd8b0a
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9
Allopurinol Sodium for Injection is indicated for the management of patients with leukemia, lymphoma, and solid tumor malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels and who cannot tolerate oral therapy.
CONTRAINDICATIONS
id: 67cf3a2b-9020-4b1c-bbcf-11f6831f9b70
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3
Patients who have developed a severe reaction to allopurinol should not be restarted on the drug.
WARNINGS
id: 6cae2d5b-f37f-4732-8c95-cd160b7e52f9
displayName: WARNINGS SECTION
FDA Article Code: 34071-1
ALLOPURINOL SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR OTHER SIGNS WHICH MAY INDICATE AN ALLERGIC REACTION. In some instances with oral allopurinol, a skin rash may be followed by more severe hypersensitivity reactions such as exfoliative, urticarial, and purpuric lesions as well as Stevens-Johnson syndrome (erythema multiforme exudativum), and/or generalized vasculitis, irreversible hepatotoxicity and, on rare occasions, death.
In patients receiving mercaptopurine or azathioprine, the concomitant administration of 300 to 600 mg of allopurinol sodium for injection per day will require a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine. Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects (see PRECAUTIONS– Drug Interactions).
A few cases of reversible clinical hepatotoxicity have been noted in patients taking oral allopurinol, and in some patients asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If anorexia, weight loss, or pruritus develop in patients on allopurinol, evaluation of liver function should be part of their diagnostic workup. In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy.
Due to the occasional occurrence of drowsiness, patients should be alerted to the need for due precaution when engaging in activities where alertness is mandatory.
The occurrence of hypersensitivity reactions to allopurinol may be increased in patients with decreased renal function receiving thiazides and allopurinol concurrently. Thus, in patients with decreased renal function, such combinations should be administered with caution.
ADVERSE REACTIONS
id: 0d19e93a-b4ba-414c-9304-7679557d0107
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4
In an uncontrolled, compassionate plea protocol, 125 of 1,378 patients reported a total of 301 adverse reactions while receiving allopurinol sodium for injection. Most of the patients had advanced malignancies or serious underlying diseases and were taking multiple concomitant medications. Side effects directly attributable to allopurinol sodium for injection were reported in 19 patients. Fifteen of these adverse experiences were allergic in nature (rash, eosinophilia, local injection site reaction). One adverse experience of severe diarrhea and one incidence of nausea were also reported as being possibly attributable to allopurinol sodium for injection. Two patients had serious adverse experiences (decreased renal function and generalized seizure) reported as being possibly attributable to allopurinol sodium for injection.
A listing of the adverse reactions regardless of causality reported from clinical trials follows:
|
Incidence Greater Than 1%:
|
|
| Cutaneous/Dermatologc:
|
rash (1.5%)
|
| Genitourinary:
|
renal failure/insufficiency (1.2%)
|
| Gastrointestinal:
|
nausea (1.3%), vomiting (1.2%)
|
|
Incidence Less Than 1%:
|
|
| Body as Whole:
|
fever, pain, chills, alopecia, infection, sepsis, enlarged abdomen, mucositis/pharyngitis, blast crisis, cellulitis, hypervolemia
|
| Cardiovascular:
|
heart failure, cardiorespiratory arrest, hypertension, pulmonary embolus, hypotension, decreased venous pressure, flushing, headache, stroke, septic shock, cardiovascular disorder, ECG abnormality, hemorrhage, bradycardia, thrombophlebitis, ventricular fibrillation
|
| Cutaneous/Dermatologic:
|
urticaria, pruritus, local injection site reaction
|
| Gastrointestinal:
|
diarrhea, gastrointestinalbleeding, hyperbilirubinemia, splenomegaly, hepatomegaly, intestinal obstruction, jaundice, flatulence, constipation, liver failure, proctitis
|
| Genitourinary:
|
hematuria, increased creatinine, oliguria, kidney function abnormality, urinary tract infection
|
| Hematologic:
|
leukopenia, marrow aplasia, thrombocytopenia, eosinophilia,neutropenia, anemia, pancytopenia, ecchymosis, bone marrow suppression, disseminated intravascular coagulation
|
| Metabolic:
|
hypocalcemia, hyperphosphatemia, hypokalemia, hyperuricemia, electrolyte abnormality, hypercalcemia, hyperglycemia, hypernatremia, hyponatremia, metabolic acidosis, edema, glycosuria, hyperkalemia, lactic acidosis, water intoxication, hypomagnesemia
|
| Neurologic:
|
seizure, status epilepticus, myoclonus, twitching, agitation, mental status changes, cerebral infarction, coma, dystonia, paralysis, tremor
|
| Pulmonary:
|
respiratory failure/insufficiency, ARDS, increased respiration rate, apnea
|
| Musculoskeletal:
|
arthralgia
|
| Other:
|
hypotonia, diaphoresis, tumor lysis syndrome
|
The most frequent adverse reaction to oral allopurinol is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with allopurinol sodium for injection should be discontinued immediately if a rash develops (see WARNINGS). For further details on hypersensitivity reactions to treatment with oral allopurinol, refer to the package insert for allopurinol tablets.
OVERDOSAGE
id: befdd6ea-a167-4b16-857e-0e3ee9acf033
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5
Massive overdosing or acute poisoning by allopurinol sodium for injection has not been reported.
In mice, the minimal lethal dose is 45 mg/kg given intravenously or 500 mg/kg orally (about 1/3 or 4 times the usual human dose on a mg/m2 basis). Hypoactivity was observed with these doses. In rats, the minimum lethal dose is 100 mg/kg i.v., and 5000 mg/kg orally (about 1.5 and 75 times the usual human dose on a mg/m2 basis).
In the management of overdosage, there is no specific antidote for allopurinol sodium for injection. There has been no clinical experience in the management of a patient who has taken massive amounts of allopurinol.
Both allopurinol and oxypurinol are dialyzable; however, the usefulness of hemodialysis or peritoneal dialysis in the management of an overdose of allopurinol sodium for injection is unknown.
HOW SUPPLIED
id: 4485898e-8fe5-4380-965b-6ff633cadd30
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5
STERILE SINGLE USE VIAL FOR INTRAVENOUS INFUSION.
Allopurinol Sodium for Injection, 50 mL flint glass vials with rubber stoppers each containing allopurinol sodium equivalent to 500 mg of allopurinol (white lyophilized powder), individually boxed, (NDC 0143-9533-01).
Store unreconstituted powder at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
For Product Inquiry call 1-877-845-0689.
Manufactured by:
HIKMA FARMACÊUTICA (PORTUGAL), S.A.
Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem SNT, PORTUGAL
Distributed by:
West-Ward Pharmaceuticals
Eatontown, NJ 07724 USA
Revised September 2015
PIN408-WES/1
VIAL LABEL
id: 69ac8c69-cb94-4771-a321-f84e99143230
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4
Allopurinol Sodium for Injection vial label
NDC 0143-9533-01
Rx only
ALLOPURINOL SODIUM FOR INJECTION
500 mg/vial
FOR INTRAVENOUS INFUSION
STERILE SINGLE USE VIAL
