Aloprim

• Bioniche Pharma USA LLC

• Mylan Institutional, Inc.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• an ACE inhibitor
• cyclophosphamide (Cytoxan)
• mercaptopurine (Purinethol)
• azathioprine (Imuran)
• blood thinners such as warfarin (Coumadin, Jantoven)
• chlorpropamide (Diabinese)
• probenecid (Benemid)
• cyclosporine (Neoral, Sandimmune)
• didanosine (Videx, Videx EC)
• sulfinpyrazone (Anturane)
• a diuretic (thiazides)
• ampicillin (Omnipen, Principen, Polycillin)
• amoxicillin (Amoxil, Trimox)

This is not a complete list of Aloprim drug interactions. Ask your doctor or pharmacist for more information.

Before receiving Aloprim, tell your doctor about all of your medical conditions including if you:

• have liver or kidney disease
• are pregnant or breastfeeding
• are allergic to any medications, foods, dyes or preservatives

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Tell your doctor if you are breastfeeding or plan to breastfeed. Aloprimis found in breastmilk. Since the effect of Aloprim on the nursing infant is unknown, caution should be used when Aloprim is given to a nursing woman.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of allopurinol injection in children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of allopurinol injection in the elderly. However, elderly patients are more likely to have age-related liver, kidney, or heart problems, which may require caution and an adjustment in the dose for patients receiving allopurinol injection.

Pregnancy

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Didanosine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Azathioprine
• Captopril
• Cyclophosphamide
• Enalapril
• Enalaprilat
• Fluorouracil
• Mercaptopurine
• Pegloticase
• Tegafur

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Cyclosporine
• Phenprocoumon
• Vidarabine
• Warfarin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bone marrow problems or
• Liver disease—Use with caution. May make these conditions worse.

• Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

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.

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

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 Aloprim (allopurinol sodium) for Injection, a well-controlled, four-way crossover study was conducted in 16 male healthy volunteers. Aloprim (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 Aloprim (allopurinol sodium) for Injection are summarized as follows:

Oxypurinol was measurable in the plasma within 10 to 15 minutes following the administration of Aloprim (allopurinol sodium) for Injection. Pharmacokinetic parameter estimates of oxypurinol following i.v. and p.o. administration of Aloprim (allopurinol sodium) for Injection are shown below:

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 Aloprim (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 Aloprim (allopurinol sodium) for Injection administration. Oral and intravenous administration of Aloprim (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 Aloprim (allopurinol sodium) for Injection.

A compassionate plea trial was conducted from 1977 through 1989 in which 718 evaluable patients with malignancies requiring treatment with cytotoxic chemotherapy, but who were unable to ingest or retain oral medication, received i.v. Aloprim (allopurinol sodium) for Injection in the U.S. Of these patients, 411 had established hyperuricemia and 307 had normal serum urate levels at the time that treatment was initiated. Normal serum uric acid levels were achieved in 68% (reduction of serum uric acid was documented in 93%) of the former, and were maintained throughout chemotherapy in 97% of the latter. Because of the study design, it was not possible to assess the impact of the treatment upon the clinical outcome of the patient groups.

In an uncontrolled, compassionate plea protocol, 125 of 1,378 patients reported a total of 301 adverse reactions while receiving Aloprim (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 Aloprim (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 Aloprim (allopurinol sodium) for Injection. Two patients had serious adverse experiences (decreased renal function and generalized seizure) reported as being possibly attributable to Aloprim (allopurinol sodium) for Injection.

A listing of the adverse reactions regardless of causality reported from clinical trials follows:

The most frequent adverse reaction to oral allopurinol is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with Aloprim (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.

NDC 67457-187-50      500 mg

Aloprim®
(allopurinol sodium)
for Injection
500 mg

equivalent to 500 mg
allopurinol

For Intravenous Infusion

Rx only Single-Use Vial

Sterile

Preparation of Solution:
Inject 25 mL Sterile Water for
Injection into vial. Swirl vial until
solution results. The solution
should be stored at 20° to 25°C
(68° to 77°F) and administration
should begin within 10 hours
after reconstitution. Further
dilution is required before
intravenous administration.

Usual Dosage and
Reconstitution Instructions:
See accompanying prescribing
information.

Store at 20° to 25°C (68° to
77°F). [See USP Controlled
Room Temperature.]

Aloprim® is a registered trademark of
Mylan Teoranta

Manufactured for:
Mylan Institutional LLC
Rockford, IL 61103 U.S.A.

Made in U.S.A.

MI:187:1C:R3

Mylan.com