Zyloprim

allopurinol

Dosage Form: tablet
PRODUCT INFORMATION

Zyloprim® (allopurinol)

100-mg Scored Tablets and

300-mg Scored Tablets

Rx Only

Zyloprim Description

Zyloprim (allopurinol) has the following structural formula:

Zyloprim is known chemically as 1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one. It is a xanthine oxidase inhibitor which is administered orally. Each scored white tablet contains 100 mg allopurinol and the inactive ingredients lactose, magnesium stearate, potato starch, and povidone. Each scored peach tablet contains 300 mg allopurinol and the inactive ingredients corn starch, FD&C Yellow No. 6 Lake, lactose, magnesium stearate, and povidone. Its solubility in water at 37°C is 80.0 mg/dL and is greater in an alkaline solution.

Zyloprim - Clinical Pharmacology

Zyloprim 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.

Zyloprim is a structural analogue of the natural purine base, hypoxanthine. It is an inhiboitor 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. Zyloprim is metabolized to the corresponding xanthine analogue, oxipurinol (alloxanthine), which also is an inhibitor of xanthine oxidase.

It has been shown that reutilization of both hypoxanthine and xanthine for nucleotide and nucleic acid synthesis is markedly enhanced when their oxidations are inhibited by Zyloprim and oxipurinol. 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 Zyloprim 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 Zyloprim. 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. Xanthine crystalluria has been reported in only three patients. Two of the patients had Lesch-Nyhan syndrome, which is characterized by excessive uric acid production combined with a deficiency of the enzyme, hypoxanthineguanine phosphoribosyltransferase (HGPRTase). This enzyme is required for the conversion of hypoxanthine, xanthine, and guanine to their respective nucleotides. The third patient had lymphosarcoma and produced an extremely large amount of uric acid because of rapid cell lysis during chemotherapy.

Zyloprim is approximately 90% absorbed from the gastrointestinal tract. Peak plasma levels generally occur at 1.5 hours and 4.5 hours for Zyloprim and oxipurinol respectively, and after a single oral dose of 300 mg Zyloprim, maximum plasma levels of about 3 mcg/mL of Zyloprim and 6.5 mcg/mL of oxipurinol are produced.

Approximately 20% of the ingested Zyloprim is excreted in the feces. Because of its rapid oxidation to oxipurinol and a renal clearance rate approximately that of glomerular filtration rate, Zyloprim has a plasma half-life of about 1 to 2 hours. Oxipurinol, however, has a longer plasma half-life (approximately 15 hours) and therefore effective xanthine oxidase inhibition is maintained over a 24-hour period with single daily doses of Zyloprim. Whereas Zyloprim is cleared essentially by glomerular filtration, oxipurinol is reabsorbed in the kidney tubules in a manner similar to the reabsorption of uric acid.

The clearance of oxipurinol is increased by uricosuric drugs, and as a consequence, the addition of a uricosuric agent reduces to some degree the inhibition of xanthine oxidase by oxipurinol and increases to some degree the urinary excretion of uric acid. In practice, the net effect of such combined therapy may be useful in some patients in achieving minimum serum uric acid levels provided the total urinary uric acid load does not exceed the competence of the patient's renal function.

Hyperuricemia may be primary, as in gout, or secondary to diseases such as acute and chronic leukemia, polycythemia vera, multiple myeloma, and psoriasis. It may occur with the use of diuretic agents, during renal dialysis, in the presence of renal damage, during starvation or reducing diets, and in the treatment of neoplastic disease where rapid resolution of tissue masses may occur. Asymptomatic hyperuricemia is not an indication for treatment with Zyloprim (see INDICATIONS AND USAGE).

Gout is a metabolic disorder which is characterized by hyperuricemia and resultant deposition of monosodium urate in the tissues, particularly the joints and kidneys. The etiology of this hyperuricemia is the overproduction of uric acid in relation to the patient's ability to excrete it. If progressive deposition of urates is to be arrested or reversed, it is necessary to reduce the serum uric acid level below the saturation point to suppress urate precipitation.

Administration of Zyloprim generally results in a fall in both serum and urinary uric acid within 2 to 3 days. The degree of this decrease can be manipulated almost at will since it is dose-dependent. A week or more of treatment with Zyloprim may be required before its full effects are manifested; likewise, uric acid may return to pretreatment levels slowly (usually after a period of 7 to 10 days following cessation of therapy). This reflects primarily the accumulation and slow clearance of oxipurinol. In some patients a dramatic fall in urinary uric acid excretion may not occur, particularly in those with severe tophaceous gout. It has been postulated that this may be due to the mobilization of urate from tissue deposits as the serum uric acid level begins to fall.

The action of Zyloprim differs from that of uricosuric agents, which lower the serum uric acid level by increasing urinary excretion of uric acid. Zyloprim reduces both the serum and urinary uric acid levels by inhibiting the formation of uric acid. The use of Zyloprim to block the formation of urates avoids the hazard of increased renal excretion of uric acid posed by uricosuric drugs.

Zyloprim can substantially reduce serum and urinary uric acid levels in previously refractory patients even in the presence of renal damage serious enough to render uricosuric drugs virtually ineffective. Salicylates may be given conjointly for their antirheumatic effect without compromising the action of Zyloprim. This is in contrast to the nullifying effect of salicylates on uricosuric drugs.

Zyloprim also inhibits the enzymatic oxidation of mercaptopurine, the sulfur-containing analogue of hypoxanthine, to 6-thiouric acid. This oxidation, which is catalyzed by xanthine oxidase, inactivates mercaptopurine. Hence, the inhibition of such oxidation by Zyloprim may result in as much as a 75% reduction in the therapeutic dose requirement of mercaptopurine when the two compounds are given together.

Indications and Usage for Zyloprim

THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT RECOMMENDED FOR THE TREATMENT OF ASYMPTOMATIC HYPERURICEMIA.

Zyloprim reduces serum and urinary uric acid concentrations. Its use should be individualized for each patient and requires an understanding of its mode of action and pharmacokinetics (see CLINICAL PHARMACOLOGY, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS).

Zyloprim is indicated in:

1. the management of patients with signs and symptoms of primary or secondary gout (acute attacks, tophi, joint destruction, uric acid lithiasis, and/or nephropathy).


2. the management of patients with leukemia, lymphoma and malignancies who are receiving cancer therapy which causes elevations of serum and urinary uric acid levels. Treatment with Zyloprim should be discontinued when the potential for overproduction of uric acid is no longer present.


3. the management of patients with recurrent calcium oxalate calculi whose daily uric acid excretion exceeds 800 mg/day in male patients and 750 mg/day in female patients. Therapy in such patients should be carefully assessed initially and reassessed periodically to determine in each case that treatment is beneficial and that the benefits outweigh the risks.

Contraindications

Patients who have developed a severe reaction to Zyloprim should not be restarted on the drug.

Warnings

Zyloprim SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR OTHER SIGNS WHICH MAY INDICATE AN ALLERGIC REACTION. In some instances 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 PURINETHOL® (mercaptopurine) or IMURAN® (azathioprine), the concomitant administration of 300 to 600 mg of Zyloprim 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 CLINICAL PHARMACOLOGY).

A few cases of reversible clinical hepatotoxicity have been noted in patients taking Zyloprim, 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 Zyloprim, 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 Zyloprim may be increased in patients with decreased renal function receiving thiazides and Zyloprim concurrently. For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely.

Precautions

General: An increase in acute attacks of gout has been reported during the early stages of administration of Zyloprim , even when normal or subnormal serum uric acid levels have been attained. Accordingly, maintenance doses of colchicine generally should be given prophylactically when Zyloprim is begun. In addition, it is recommended that the patient start with a low dose of Zyloprim (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but without exceeding the maximum recommended dose (800 mg per day). The use of colchicine or anti-inflammatory agents may be required to suppress gouty attacks in some cases. The attacks usually become shorter and less severe after several months of therapy. The mobilization of urates from tissue deposits which cause fluctuations in the serum uric acid levels may be a possible explanation for these episodes. Even with adequate therapy with Zyloprim, it may require several months to deplete the uric acid pool sufficiently to achieve control of the acute attacks.

A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable to (1) avoid the theoretical possibility of formation of xanthine calculi under the influence of therapy with Zyloprim and (2) help prevent renal precipitation of urates in patients receiving concomitant uricosuric agents.

Some patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during administration of Zyloprim. Although the mechanism responsible for this has not been established, patients with impaired renal function should be carefully observed during the early stages of administration of Zyloprim and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist.

Renal failure in association with administration of Zyloprim has been observed among patients with hyperuricemia secondary to neoplastic diseases. Concurrent conditions such as multiple myeloma and congestive myocardial disease were present among those patients whose renal dysfunction increased after Zyloprim was begun. Renal failure is also frequently associated with gouty nephropathy and rarely with hypersensitivity reactions associated with Zyloprim. Albuminuria has been observed among patients who developed clinical gout following chronic glomerulonephritis and chronic pyelonephritis.

Patients with decreased renal function require lower doses of Zyloprim than those with normal renal function. Lower than recommended doses should be used to initiate therapy in any patients with decreased renal function and they should be observed closely during the early stages of administration of Zyloprim . In patients with severely impaired renal function or decreased urate clearance, the half-life of oxipurinol in the plasma is greatly prolonged. Therefore, a dose of 100 mg per day or 300 mg twice a week, or perhaps less, may be sufficient to maintain adequate xanthine oxidase inhibition to reduce serum urate levels.

Bone marrow depression has been reported in patients receiving Zyloprim, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as 6 weeks to as long as 6 years after the initiation of therapy of Zyloprim . Rarely, a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving Zyloprim alone.

Information for Patients: Patients should be informed of the following:

(1) They should be cautioned to discontinue Zyloprim and to consult their physician immediately at the first sign of a skin rash, painful urination, blood in the urine, irritation of the eyes, or swelling of the lips or mouth. (2) They should be reminded to continue drug therapy prescribed for gouty attacks since optimal benefit of Zyloprim may be delayed for 2 to 6 weeks. (3) They should be encouraged to increase fluid intake during therapy to prevent renal stones. (4) If a single dose of Zyloprim is occasionally forgotten, there is no need to double the dose at the next scheduled time. (5) There may be certain risks associated with the concomitant use of Zyloprim and dicumarol, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, and thiazide diuretics, and they should follow the instructions of their physician. (6) Due to the occasional occurrence of drowsiness, patients should take precautions when engaging in activities where alertness is mandatory. (7) Patients may wish to take Zyloprim after meals to minimize gastric irritation.

Laboratory Tests: The correct dosage and schedule for maintaining the serum uric acid within the normal range is best determined by using the serum uric acid as an index.

In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy (see WARNINGS).

Zyloprim and its primary active metabolite, oxipurinol, are eliminated by the kidneys; therefore, changes in renal function have a profound effect on dosage. In patients with decreased renal function or who have concurrent illnesses which can affect renal function such as hypertension and diabetes mellitus, periodic laboratory parameters of renal function, particularly BUN and serum creatinine or creatinine clearance, should be performed and the patient's dosage of Zyloprim reassessed.

The prothrombin time should be reassessed periodically in the patients receiving dicumarol who are given Zyloprim.

Drug Interactions: In patients receiving PURINETHOL (mercaptopurine) or IMURAN (azathioprine), the concomitant administration of 300 to 600 mg of Zyloprim 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 CLINICAL PHARMACOLOGY).

It has been reported that Zyloprim prolongs the half-life of the anticoagulant, dicumarol. The clinical basis of this drug interaction has not been established but should be noted when Zyloprim is given to patients already on dicumarol therapy.

Since the excretion of oxipurinol is similar to that of urate, uricosuric agents, which increase the excretion of urate, are also likely to increase the excretion of oxipurinol and thus lower the degree of inhibition of xanthine oxidase. The concomitant administration of uricosuric agents and Zyloprim has been associated with a decrease in the excretion of oxypurines (hypoxanthine and xanthine) and an increase in urinary uric acid excretion compared with that observed with Zyloprim alone. Although clinical evidence to date has not demonstrated renal precipitation of oxypurines in patients either on Zyloprim alone or in combination with uricosuric agents, the possibility should be kept in mind.

The reports that the concomitant use of Zyloprim and thiazide diuretics may contribute to the enhancement of allopurinol toxicity in some patients have been reviewed in an attempt to establish a cause-and-effect relationship and a mechanism of causation. Review of these case reports indicates that the patients were mainly receiving thiazide diuretics for hypertension and that tests to rule out decreased renal function secondary to hypertensive nephropathy were not often performed. In those patients in whom renal insufficiency was documented, however, the recommendation to lower the dose of Zyloprim was not followed. Although a causal mechanism and a cause-and-effect relationship have not been established, current evidence suggests that renal function should be monitored in patients on thiazide diuretics and Zyloprim even in the absence of renal failure, and dosage levels should be even more conservatively adjusted in those patients on such combined therapy if diminished renal function is detected.

An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with Zyloprim compared to patients who are not receiving both drugs. The cause of the reported association has not been established.

Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except leukemia, in the presence of Zyloprim. However, in a well-controlled study of patients with lymphoma on combination therapy, Zyloprim did not increase the marrow toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine.

Tolbutamide's conversion to inactive metabolites has been shown to be catalyzed by xanthine oxidase from rat liver. The clinical significance, if any, of these observations is unknown.

Chlorpropamide's plasma half-life may be prolonged by Zyloprim, since Zyloprim and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if Zyloprim and chlorpropamide are given concomitantly in the presence of renal insufficiency.

Rare reports indicate that cyclosporine levels may be increased during concomitant treatment with Zyloprim. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are co-administered.

Drug/Laboratory Test Interactions: Zyloprim is not known to alter the accuracy of laboratory tests.

Pregnancy

Teratogenic Effects: Pregnancy Category C. Reproductive studies have been performed in rats and rabbits at doses up to twenty times the usual human dose (5 mg/kg per day), and it was concluded that there was no impaired fertility or harm to the fetus due to allopurinol. There is a published report of a study in pregnant mice given 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13. There were increased numbers of dead fetuses in dams given 100 mg/kg allopurinol but not in those given 50 mg/kg. There were increased numbers of external malformations in fetuses at both doses of allopurinol on gestation day 10 and increased numbers of skeletal malformations in fetuses at both doses on gestation day 13. It cannot be determined whether this represented a fetal effect or an effect secondary to maternal toxicity. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Experience with Zyloprim during human pregnancy has been limited partly because women of reproductive age rarely require treatment with Zyloprim. There are two unpublished reports and one published paper of women giving birth to normal offspring after receiving Zyloprim during pregnancy.

Nursing Mothers: Allopurinol and oxipurinol have been found in the milk of a mother who was receiving Zyloprim. Since the effect of allopurinol on the nursing infant is unknown, caution should be exercised when Zyloprim is administered to a nursing woman.

Pediatric Use: Zyloprim is rarely indicated for use in children with the exception of those with hyperuricemia secondary to malignancy or to certain rare inborn errors of purine metabolism (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION).

Adverse Reactions

Data upon which the following estimates of incidence of adverse reactions are made are derived from experiences reported in the literature, unpublished clinical trials and voluntary reports since marketing of Zyloprim (allopurinol) began. Past experience suggested that the most frequent event following the initiation of allopurinol treatment was an increase in acute attacks of gout (average 6% in early studies). An analysis of current usage suggests that the incidence of acute gouty attacks has diminished to less than 1%. The explanation for this decrease has not been determined but may be due in part to initiating therapy more gradually (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

The most frequent adverse reaction to Zyloprim is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with Zyloprim should be discontinued immediately if a rash develops (see WARNINGS). Some patients with the most severe reaction also had fever, chills, arthralgias, cholestatic jaundice, eosinophilia and mild leukocytosis or leukopenia. Among 55 patients with gout treated with Zyloprim for 3 to 34 months (average greater than 1 year) and followed prospectively, Rundles observed that 3% of patients developed a type of drug reaction which was predominantly a pruritic maculopapular skin eruption, sometimes scaly or exfoliative. However, with current usage, skin reactions have been observed less frequently than 1%. The explanation for this decrease is not obvious. The incidence of skin rash may be increased in the presence of renal insufficiency. The frequency of skin rash among patients receiving ampicillin or amoxicillin concurrently with Zyloprim has been reported to be increased (see PRECAUTIONS).

Most Common Reactions* Probably Causally Related:

 

Gastrointestinal: Diarrhea, nausea, alkaline phosphatase increase, SGOT/SGPT increase.

 

Metabolic and Nutritional: Acute attacks of gout.

 

Skin and Appendages: Rash, maculopapular rash.

 

*Early clinical studies and incidence rates from early clinical experience with Zyloprim suggested that these adverse reactions were found to occur at a rate of greater than 1%. The most frequent event observed was acute attacks of gout following the initiation of therapy. Analyses of current usage suggest that the incidence of these adverse reactions is now less than 1%. The explanation for this decrease has not been determined, but it may be due to following recommended usage (see ADVERSE REACTIONS introduction, INDICATIONS AND USAGE, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Incidence Less Than 1% Probably Causally Related:

 

Body As a Whole: Ecchymosis, fever, headache.

 

Cardiovascular: Necrotizing angiitis, vasculitis.

 

Gastrointestinal: Hepatic necrosis, granulomatous hepatitis, hepatomegaly, hyperbilirubinemia, cholestatic jaundice, vomiting, intermittent abdominal pain, gastritis, dyspepsia.

 

Hemic and Lymphatic: Thrombocytopenia, eosinophilia, leukocytosis, leukopenia.

 

Musculoskeletal: Myopathy, arthralgias.

 

Nervous: Peripheral neuropathy, neuritis, paresthesia, somnolence.

 

Respiratory: Epistaxis.

 

Skin and Appendages: Erythema multiforme exudativum (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), hypersensitivity vasculitis, purpura, vesicular bullous dermatitis, exfoliative dermatitis, eczematoid dermatitis, pruritus, urticaria, alopecia, onycholysis, lichen planus.

 

Special Senses: Taste loss/perversion.

 

Urogenital: Renal failure, uremia (see PRECAUTIONS).

Incidence Less Than 1% Causal Relationship Unknown:

 

Body As a Whole: Malaise.

 

Cardiovascular: Pericarditis, peripheral vascular disease, thrombophlebitis, bradycardia, vasodilation.

 

Endocrine: Infertility (male), hypercalcemia, gynecomastia (male).

 

Gastrointestinal: Hemorrhagic pancreatitis, gastrointestinal bleeding, stomatitis, salivary gland swelling, hyperlipidemia, tongue edema, anorexia.

 

Hemic and Lymphatic: Aplastic anemia, agranulocytosis, eosinophilic fibrohistiocytic lesion of bone marrow, pancytopenia, prothrombin decrease, anemia, hemolytic anemia, reticulocytosis, lymphadenopathy, lymphocytosis.

 

Musculoskeletal: Myalgia.

 

Nervous: Optic neuritis, confusion, dizziness, vertigo, foot drop, decrease in libido, depression, amnesia, tinnitus, asthenia, insomnia.

 

Respiratory: Bronchospasm, asthma, pharyngitis, rhinitis.

 

Skin and Appendages: Furunculosis, facial edema, sweating, skin edema.

 

Special Senses: Cataracts, macular retinitis, iritis, conjunctivitis, amblyopia.

 

Urogenital: Nephritis, impotence, primary hematuria, albuminuria.

Overdosage

Massive overdosing or acute poisoning by Zyloprim has not been reported.

In mice, the 50% lethal dose (LD50) is 160 mg/kg given intraperitoneally (IP) with deaths delayed up to 5 days and 700 mg/kg orally (PO) (approximately 140 times the usual human dose) with deaths delayed up to 3 days. In rats, the acute LD50 is 750 mg/kg IP and 6000 mg/kg PO (approximately 1200 times the human dose).

In the management of overdosage there is no specific antidote for Zyloprim. There has been no clinical experience in the management of a patient who has taken massive amounts of Zyloprim.

Both Zyloprim and oxipurinol are dialyzable; however, the usefulness of hemodialysis or peritoneal dialysis in the management of an overdose of Zyloprim is unknown.

Zyloprim Dosage and Administration

The dosage of Zyloprim to accomplish full control of gout and to lower serum uric acid to normal or near-normal levels varies with the severity of the disease. The average is 200 to 300 mg/day for patients with mild gout and 400 to 600 mg/day for those with moderately severe tophaceous gout. The appropriate dosage may be administered in divided doses or as a single equivalent dose with the 300-mg tablet. Dosage requirements in excess of 300 mg should be administered in divided doses. The minimal effective dosage is 100 to 200 mg daily and the maximal recommended dosage is 800 mg daily. To reduce the possibility of flare-up of acute gouty attacks, it is recommended that the patient start with a low dose of Zyloprim (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but without exceeding the maximal recommended dosage.

Normal serum urate levels are usually achieved in 1 to 3 weeks. The upper limit of normal is about 7 mg/dL for men and postmenopausal women and 6 mg/dL for premenopausal women. Too much reliance should not be placed on a single serum uric acid determination since, for technical reasons, estimation of uric acid may be difficult. By selecting the appropriate dosage and, in certain patients, using uricosuric agents concurrently, it is possible to reduce serum uric acid to normal or, if desired, to as low as 2 to 3 mg/dL and keep it there indefinitely.

While adjusting the dosage of Zyloprim in patients who are being treated with colchicine and/or anti-inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute gouty attacks for several months.

In transferring a patient from a uricosuric agent to Zyloprim, the dose of the uricosuric agent should be gradually reduced over a period of several weeks and the dose of Zyloprim gradually increased to the required dose needed to maintain a normal serum uric acid level.

It should also be noted that Zyloprim is generally better tolerated if taken following meals. A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable.

Since Zyloprim and its metabolites are primarily eliminated only by the kidney, accumulation of the drug can occur in renal failure, and the dose of Zyloprim should consequently be reduced. With a creatinine clearance of 10 to 20 mL/min, a daily dosage of 200 mg of Zyloprim is suitable. When the creatinine clearance is less than 10 mL/min, the daily dosage should not exceed 100 mg. With extreme renal impairment (creatinine clearance less than 3 mL/min) the interval between doses may also need to be lengthened.

The correct size and frequency of dosage for maintaining the serum uric acid just within the normal range is best determined by using the serum uric acid level as an index.

For the prevention of uric acid nephropathy during the vigorous therapy of neoplastic disease, treatment with 600 to 800 mg daily for 2 or 3 days is advisable together with a high fluid intake. Otherwise similar considerations to the above recommendations for treating patients with gout govern the regulation of dosage for maintenance purposes in secondary hyperuricemia.

The dose of Zyloprim recommended for management of recurrent calcium oxalate stones in hyperuricosuric patients is 200 to 300 mg/day in divided doses or as the single equivalent. This dose may be adjusted up or down depending upon the resultant control of the hyperuricosuria based upon subsequent 24 hour urinary urate determinations. Clinical experience suggests that patients with recurrent calcium oxalate stones may also benefit from dietary changes such as the reduction of animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium intake, as well as an increase in oral fluids and dietary fiber.

Children, 6 to 10 years of age, with secondary hyperuricemia associated with malignancies may be given 300 mg Zyloprim daily while those under 6 years are generally given 150 mg daily. The response is evaluated after approximately 48 hours of therapy and a dosage adjustment is made if necessary.

How is Zyloprim Supplied

100-mg (white) scored, flat cylindrical tablets imprinted with “Zyloprim 100” on a raised hexagon, bottles of 100 (NDC 65483-991-10).

Store at 15° to 25°C (59° to 77°F) in a dry place.

300-mg (peach) scored, flat, cylindrical tablets imprinted with “Zyloprim 300” on a raised hexagon, bottles of 100 (NDC 65483-993-10) and 500 (NDC 65483-993-50).

Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light.

PROMETHEUS LABORATORIES INC.

Manufactured by

DSM Pharmaceuticals, Inc.

Greenville, NC 27834

for Prometheus Laboratories Inc.

San Diego, CA 92121

October 2003

ZY004B03

mg 100 Tablets Bottle

100 Tablets NDC 65483-991-10

Zyloprim®

(allopurinol)

Each scored tablet contains

100 mg

Rx Only

PROMETHEUS LABORATORIES INC.

Manufactured by DSM Pharmaceuticals, Inc., Greenville, NC 27834

For Prometheus Laboratories Inc., San Diego, CA 92121

October 2003 650392

mg 100 Tablets Bottle

100 Tablets NDC 65483-993-10

Zyloprim®

(allopurinol)

Each scored tablet contains

300 mg

Rx Only

PROMETHEUS LABORATORIES INC.

Manufactured by DSM Pharmaceuticals, Inc., Greenville, NC 27834

For Prometheus Laboratories Inc., San Diego, CA 92121

October 2003 650390

Zyloprim  allopurinol  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 65483-991 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength allopurinol (allopurinol) allopurinol 100 mg

Inactive Ingredients Ingredient Name Strength lactose   magnesium stearate   starch, potato   povidone

Product Characteristics Color white (white) Score 2 pieces Shape ROUND (ROUND) Size 3mm Flavor Imprint Code Zyloprim;100 Contains

Packaging # NDC Package Description Multilevel Packaging 1 65483-991-10 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA016084	08/19/1966

Zyloprim  allopurinol  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 65483-993 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength allopurinol (allopurinol) allopurinol 300 mg

Inactive Ingredients Ingredient Name Strength starch, corn   FD&C Yellow No. 6   lactose   magnesium stearate   starch, potato   povidone

Product Characteristics Color orange (orange) Score 2 pieces Shape ROUND (ROUND) Size 4mm Flavor Imprint Code Zyloprim;300 Contains

Packaging # NDC Package Description Multilevel Packaging 1 65483-993-10 100 TABLET In 1 BOTTLE None 2 65483-993-50 500 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA016084	08/19/1966

Labeler - Prometheus Laboratories Inc. (967000860)

Establishment
Name	Address	ID/FEI	Operations
DSM Pharmaceuticals Inc.		076301910	MANUFACTURE

Revised: 11/2009Prometheus Laboratories Inc.

More Zyloprim resources

• Zyloprim Side Effects (in more detail)
• Zyloprim Dosage
• Zyloprim Use in Pregnancy & Breastfeeding
• Drug Images
• Zyloprim Drug Interactions
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Desmotabs 0.2mg

1. Name Of The Medicinal Product

DESMOTABS^® 0.2mg

2. Qualitative And Quantitative Composition

Each tablet contains 0.2mg desmopressin acetate

For excipients, see 6.1

3. Pharmaceutical Form

Tablet

Uncoated, white, round, convex tablets scored on one side and engraved '0.2' on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Desmopressin tablets are indicated for the treatment of primary nocturnal enuresis.

4.2 Posology And Method Of Administration

Children (from 5 years of age) and adults (up to 65 years of age) with normal urine concentrating ability who have primary nocturnal enuresis should take 0.2mg at bedtime and only if needed should the dose be increased to 0.4mg.

The need for continued treatment should be reassessed after 3 months by means of a period of at least 1 week without desmopressin tablets.

4.3 Contraindications

Desmopressin tablets are contraindicated in cases of cardiac insufficiency and other conditions requiring treatment with diuretic agents. Desmopressin tablets should only be used in patients with normal blood pressure.

Before prescribing desmopressin tablets the diagnoses of psychogenic polydipsia and alcohol abuse should be excluded.

Desmopressin should not be prescribed to patients over the age of 65 for the treatment of primary nocturnal enuresis.

4.4 Special Warnings And Precautions For Use

Care should be taken with patients who have reduced renal function and/or cardiovascular disease or cystic fibrosis. In chronic renal disease the antidiuretic effect of desmopressin tablets would be less than normal.

When desmopressin tablets are used for the treatment of enuresis, fluid intake must be limited from 1 hour before taking the tablets at bedtime until the next morning and in any case for a minimum of 8 hours after administration.

Patients being treated for primary nocturnal enuresis should be warned to avoid ingesting water while swimming and to discontinue desmopressin tablets during an episode of vomiting and/or diarrhoea until their fluid balance is once again normal.

Precautions to prevent fluid overload must be taken in:

- conditions characterised by fluid and/or electrolyte imbalance

- patients at risk for increased intracranial pressure

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Substances which are known to induce SIADH e.g. tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine and carbamazepine, may cause an additive antidiuretic effect leading to an increased risk of water retention and/or hyponatraemia.

NSAIDs may induce water retention and/or hyponatraemia.

Concomitant treatment with loperamide may result in a 3-fold increase of desmopressin plasma concentrations, which may lead to an increased risk of water retention and/or hyponatraemia. Although not investigated, other drugs slowing transport might have the same effect.

A standardised 27% fat meal significantly decreased the absorption (rate and extent) of a 0.4mg dose of oral desmopressin. Although it did not significantly affect the pharmacodynamic effect (urine production and osmolality), there is the potential for this to occur at lower doses. If a diminution of effect is noted, then the effect of food should be considered before increasing the dose.

4.6 Pregnancy And Lactation

Pregnancy:

Data on a limited number (n=53) of exposed pregnancies in women with diabetes insipidus indicate rare cases of malformations in children treated during pregnancy. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development.

Caution should be exercised when prescribing to pregnant women. Blood pressure monitoring is recommended due to the increased risk of pre-eclampsia.

Lactation:

Results from analyses of milk from nursing mothers receiving high dose desmopressin (300 micrograms intranasally) indicate that the amounts of desmopressin that may be transferred to the child are considerably less than the amounts required to influence diuresis.

4.7 Effects On Ability To Drive And Use Machines

None

4.8 Undesirable Effects

Side-effects include headache, stomach pain and nausea. Isolated cases of allergic skin reactions and more severe general allergic reactions have been reported. Very rare cases of emotional disorders including aggression in children have been reported. Treatment with desmopressin without concomitant reduction of fluid intake may lead to water retention/hyponatraemia with accompanying symptoms of headache, nausea, vomiting, weight gain, decreased serum sodium and in serious cases, convulsions.

4.9 Overdose

An overdose of desmopressin tablets leads to a prolonged duration of action with an increased risk of water retention and/or hyponatraemia.

Treatment:

Although the treatment of hyponatraemia should be individualised, the following general recommendations can be given. Hyponatraemia is treated by discontinuing the desmopressin treatment, fluid restriction and symptomatic treatment if needed.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

In its main biological effects, desmopressin does not differ qualitatively from vasopressin. However, desmopressin is characterised by a high antidiuretic activity whereas the uterotonic and vasopressor actions are extremely low.

In a modelling study in which intravenous desmopressin was infused over two hours in healthy adult male subjects, the EC₅₀ value was calculated as 1.7pg/ml based on urinary osmolality and 2.4pg/ml based on urinary volume.

5.2 Pharmacokinetic Properties

The absolute bioavailability of orally administered desmopressin varies between 0.08% and 0.16%. Mean maximum plasma concentration is reached within 2 hours. The distribution volume is 0.2 – 0.32 l/kg. Desmopressin does not cross the blood-brain barrier. The oral terminal half-life varies between 2.0 and 3.11 hours.

After oral administration of a single dose of 2 x 200 micrograms desmopressin tablets to healthy subjects, 25% of the subjects had plasma concentrations of desmopressin above 1pg/ml up to at least 14 hours post dosing.

In in vitro studies in human liver microsome preparations, it has been shown that no significant amount of desmopressin is metabolised, and thus human liver metabolism in vivo is not likely to occur. Consequently it is also unlikely that desmopressin will interact with drugs affecting hepatic metabolism. However, formal in vivo interaction studies have not been performed.

About 65% of the amount of desmopressin absorbed after oral administration could be recovered in the urine within 24 hours.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose monohydrate

Potato starch

Povidone

Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Do not store above 25°C. Keep the container tightly closed.

6.5 Nature And Contents Of Container

30ml High Density Polyethylene (HDPE) bottle with a tamper-proof, twist-off polypropylene (PP) closure with a silica gel desiccant insert. Each bottle contains 7, 30 or 90 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Ferring Pharmaceuticals Ltd.,

The Courtyard

Waterside Drive

Langley

Berkshire SL3 6EZ.

8. Marketing Authorisation Number(S)

PL 03194/0046

9. Date Of First Authorisation/Renewal Of The Authorisation

19^th April 1999.

10. Date Of Revision Of The Text

May 2008

Synvisc

Generic Name: hylan G-F 20 (HI lan G F 20)

Brand Names: Synvisc, Synvisc-One

What is hylan G-F 20?

Hylan G-F 20 is similar to the fluid that surrounds the joints in your body. This fluid acts as a lubricant and shock absorber for the joints.

Hylan G-F 20 is used to treat knee pain caused by osteoarthritis.

Hylan G-F 20 is usually given after other arthritis medications have been tried without successful treatment of symptoms.

Hylan G-F 20 may also be used for purposes not listed in this medication guide.

What is the most important information I should know about hylan G-F 20?

You should not receive hylan G-F 20 if you are allergic to it, or if you have an infection in your knee or in the skin around your knee.

Before you receive a hylan G-F 20 injection, tell your doctor if you have blood clots or circulation problems in your legs, or an allergy to birds, feathers, or egg products.

For at least 48 hours after your injection, avoid jogging, strenuous activity, high-impact sports, or standing for longer than 1 hour at a time.

Call your doctor at once if you have severe pain or swelling around the knee after the injection.

What should I discuss with my health care provider before receiving hylan G-F 20?

You should not receive hylan G-F 20 if you are allergic to it, or if you have an infection in your knee or in the skin around your knee.

To make sure you can safely receive hylan G-F 20, tell your doctor if you have:

• 
  

  blood clots or circulation problems in your legs; or

  
  


• 
  

  an allergy to birds, feathers, or egg products.

  
  

It is not known whether hylan G-F 20 will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. It is not known whether hylan G-F 20 passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby. Hylan G-F 20 is generally not used in anyone younger than 21 years old.

How is hylan G-F 20 given?

Hylan G-F 20 is injected directly into your knee joint. A healthcare provider will give you this injection.

Hylan G-F 20 is usually given once every week for 3 weeks. Follow your doctor's dosing instructions very carefully.

To prevent pain and swelling, your doctor may recommend resting your knee or applying ice for a short time after your injection.

What happens if I miss a dose?

Call your doctor for instructions if you miss an appointment for your hylan G-F 20 injection.

What happens if I overdose?

Since this medication is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

What should I avoid after receiving hylan G-F 20?

For at least 48 hours after your injection, avoid jogging, strenuous activity, or high-impact sports such as soccer or tennis. Also avoid weight-bearing activity or standing for longer than 1 hour at a time. Ask your doctor how long to wait before you resume these activities.

Hylan G-F 20 side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Call your doctor at once if you have severe pain or swelling around the knee after the injection.

Less serious side effects may include:

• 
  

  warmth, pain, stiffness, swelling, or puffiness where the medicine was injected;

  
  


• 
  

  muscle pain, trouble walking;

  
  


• 
  

  fever, chills, nausea;

  
  


• 
  

  numbness or tingly feeling;

  
  


• 
  

  headache, dizziness;

  
  


• 
  

  tired feeling; or

  
  


• 
  

  itching or skin irritation around the knee.

  
  

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect hylan G-F 20?

There may be other drugs that can interact with hylan G-F 20. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Synvisc resources

• Synvisc Side Effects (in more detail)
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• Synvisc Drug Interactions
• Synvisc Support Group
• 6 Reviews for Synvisc - Add your own review/rating

• Synvisc Advanced Consumer (Micromedex) - Includes Dosage Information


• Synvisc Solution MedFacts Consumer Leaflet (Wolters Kluwer)


• Synvisc Consumer Overview


• Hylan G-F 20

Compare Synvisc with other medications

• Osteoarthritis

Where can I get more information?

• Your doctor can provide more information about hylan G-F 20.

See also: Synvisc side effects (in more detail)

Foscarnet

Dosage Form: injection, solution
Foscarnet SODIUM INJECTION

24 mg/mL

Rx only

WARNING

RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF Foscarnet SODIUM INJECTION. FREQUENT MONITORING OF SERUM CREATININE, WITH DOSE ADJUSTMENT FOR CHANGES IN RENAL FUNCTION, AND ADEQUATE HYDRATION WITH ADMINISTRATION OF Foscarnet SODIUM INJECTION, IS IMPERATIVE. (See ADMINISTRATION section; Hydration.)

SEIZURES, RELATED TO ALTERATIONS IN PLASMA MINERALS AND ELECTROLYTES, HAVE BEEN ASSOCIATED WITH Foscarnet SODIUM INJECTION TREATMENT. THEREFORE, PATIENTS MUST BE CAREFULLY MONITORED FOR SUCH CHANGES AND THEIR POTENTIAL SEQUELAE. MINERAL AND ELECTROLYTE SUPPLEMENTATION MAY BE REQUIRED.

Foscarnet SODIUM INJECTION IS INDICATED FOR USE ONLY IN IMMUNOCOMPROMISED PATIENTS WITH CMV RETINITIS AND MUCOCUTANEOUS ACYCLOVIR-RESISTANT HSV INFECTIONS. (See INDICATIONS section.)

Foscarnet Description

The chemical name of Foscarnet sodium is phosphonoformic acid, trisodium salt. Foscarnet sodium is a white, crystalline powder containing 6 equivalents of water of hydration with a molecular formula of Na3CO5P•6 H2O and a molecular weight of 300.1. The structural formula is:

Foscarnet sodium has the potential to chelate divalent metal ions, such as calcium and magnesium, to form stable coordination compounds. Foscarnet sodium injection is a sterile, isotonic aqueous solution for intravenous administration only. The solution is clear and colorless. Each milliliter of Foscarnet sodium injection contains 24 mg of Foscarnet sodium hexahydrate in Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH of the solution to 7.4. Foscarnet sodium injection contains no preservatives.

VIROLOGY 

Mechanism of Action: Foscarnet sodium is an organic analogue of inorganic pyrophosphate that inhibits replication of herpesviruses in vitro including cytomegalovirus (CMV) and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2).

Foscarnet sodium exerts its antiviral activity by a selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases at concentrations that do not affect cellular DNA polymerases. Foscarnet sodium does not require activation (phosphorylation) by thymidine kinase or other kinases and therefore is active in vitro against HSV TK deficient mutants and CMV UL97 mutants. Thus, HSV strains resistant to acyclovir or CMV strains resistant to ganciclovir may be sensitive to Foscarnet sodium. However, acyclovir or ganciclovir resistant mutants with alterations in the viral DNA polymerase may be resistant to Foscarnet sodium and may not respond to therapy with Foscarnet sodium. The combination of Foscarnet sodium and ganciclovir has been shown to have enhanced activity in vitro.

Antiviral Activity in vitro and in vivo : The quantitative relationship between the in vitro susceptibility of human cytomegalovirus (CMV) or herpes simplex virus 1 and 2 (HSV-1 and HSV-2) to Foscarnet sodium and clinical response to therapy has not been established and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending on the assay method used, cell type employed and the laboratory performing the test. A number of sensitive viruses and their IC50 values are listed below (Table 1).

TABLE 1
Foscarnet Inhibition of virus multiplication in cell culture
Virus	IC50 (μM)
CMV	50-800*
HSV-1, HSV-2	10-130
Ganciclovir resistant CMV	190
HSV-TK negative mutant	67
HSV-DNA polymerase mutants	5-443
* Mean = 269 μM

Statistically significant decreases in positive CMV cultures from blood and urine have been demonstrated in two studies (FOS-03 and ACTG-015/915) of patients treated with Foscarnet sodium. Although median time to progression of CMV retinitis was increased in patients treated with Foscarnet sodium, reductions in positive blood or urine cultures have not been shown to correlate with clinical efficacy in individual patients.

TABLE 2
Blood and Urine Culture Results from CMV Retinitis Patients*
Blood		+CMV	-CMV
Baseline		27	34
End of Induction **		1	60
Urine		+CMV	-CMV
Baseline		52	6
End of Induction**		21	37
* A total of 77 patients was treated with Foscarnet sodium in two clinical trials (FOS-03 and ACTG-015/915). Not all patients had blood or urine cultures done and some patients had results from both cultures. ** (60 mg/kg Foscarnet sodium injection TID for 2 to 3 weeks).

Resistance: Strains of both HSV and CMV that are resistant to Foscarnet sodium can be readily selected in vitro by passage of wild type virus in the presence of increasing concentrations of the drug. All Foscarnet sodium resistant mutants are known to be generated through mutation in the viral DNA polymerase gene. CMV strains with double mutations conferring resistance to both Foscarnet sodium and ganciclovir have been isolated from patients with AIDS. The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.

Foscarnet - Clinical Pharmacology

Pharmacokinetics: The pharmacokinetics of Foscarnet have been determined after administration as an intermittent intravenous infusion during induction therapy in AIDS patients with CMV retinitis. Observed plasma Foscarnet concentrations in four studies (FOS-01, ACTG-015, FP48PK, FP49PK) are summarized in Table 3:

TABLE 3
Foscarnet Pharmacokinetic Characteristics*
* Values expressed as mean ± S.D. (number of subjects studied) for each parameter † 50 mg/kg Q8h for 28 days, samples taken 3 hrs after end of 1 hr infusion (Astra Report 815-04 AC025-1) ‡ 90 mg/kg Q12h for 28 days, samples taken 1 hr after end of 2 hr infusion (Hengge et al., 1993)
Parameter		60 mg/kg Q8h	90 mg/kg Q12h
Cmax at steady-state (μM)		589 ± 192 (24)	623 ± 132 (19)
Ctrough at steady-state (μM)		114 ± 91 (24)	63 ± 57 (17)
Volume of Distribution (L/kg)		0.41 ± 0.13 (12)	0.52 ± 0.20 (18)
Plasma half-life (hr)		4.0 ± 2.0 (24)	3.3 ± 1.4 (18)
Systemic clearance (L/hr)		6.2 ± 2.1 (24)	7.1 ± 2.7 (18)
Renal clearance (L/hr)		5.6 ± 1.9 (5)	6.4 ± 2.5 (13)
CSF:plasma ratio		0.69 ± 0.19 (9)†	0.66 ± 0.11 (5)‡

Distribution: In vitro studies have shown that 14 to 17% of Foscarnet is protein bound at plasma drug concentrations of 1 to 1000 μM.

The Foscarnet terminal half-life determined by urinary excretion was 87.5 ± 41.8 hours, possibly due to release of Foscarnet from bone. Postmortem data on several patients in European clinical trials provide evidence that Foscarnet does accumulate in bone in humans; however, the extent to which this occurs has not been determined. In animal studies (mice), 40% of an intravenous dose of Foscarnet sodium was deposited in bone in young animals and 7% was deposited in adult animals.

Special Populations:

Adults with Impaired Renal Function: The pharmacokinetic properties of Foscarnet have been determined in a small group of adult subjects with normal and impaired renal function, as summarized in Table 4:

TABLE 4
Pharmacokinetic Parameters (mean ± S.D.) After a Single 60 mg/kg Dose of Foscarnet Sodium in 4 Groups* of Adults with Varying Degrees of Renal Function
* Group 1 patients had normal renal function defined as a creatinine clearance (CrCl) of >80 mL/min, Group 2 CrCl was 50 to 80 mL/min, Group 3 CrCl was 25 to 49 mL/min and Group 4 CrCl was 10 to 24 mL/min.
Parameter	Group 1 (N=6)	Group 2 (N=6)	Group 3 (N=6)	Group 4 (N=4)
Creatinine clearance (mL/min)	108 ± 16	68 ± 8	34 ± 9	20 ± 4
Foscarnet CL (mL/min/kg)	2.13 ± 0.71	1.33 ± 0.43	0.46 ± 0.14	0.43 ± 0.26
Foscarnet half-life (hr)	1.93 ± 0.12	3.35 ± 0.87	13.0 ± 4.05	25.3 ± 18.7

Total systemic clearance (CL) of Foscarnet decreased and half-life increased with diminishing renal function (as expressed by creatinine clearance). Based on these observations, it is necessary to modify the dosage of Foscarnet in patients with renal impairment (see DOSAGE AND ADMINISTRATION).

Clinical Studies

CMV Retinitis: A prospective, randomized, controlled clinical trial (FOS-03) was conducted in 24 patients with AIDS and CMV retinitis comparing treatment with Foscarnet sodium to no treatment. Patients received induction treatment of Foscarnet sodium, 60 mg/kg every 8 hours for 3 weeks, followed by maintenance treatment with 90 mg/kg/day until retinitis progression (appearance of a new lesion or advancement of the border of a posterior lesion greater than 750 microns in diameter). All diagnoses and determinations of retinitis progression were made from masked reading of retinal photographs. The 13 patients randomized to treatment with Foscarnet sodium had a significant delay in progression of CMV retinitis compared to untreated controls. Median times to retinitis progression from study entry were 93 days (range 21 to >364) and 22 days (range 7 to 42), respectively.

In another prospective clinical trial of CMV retinitis in patients with AIDS (ACTG-915), 33 patients were treated with two to three weeks of Foscarnet sodium induction (60 mg/kg TID) and then randomized to either 90 mg/kg/day or 120 mg/kg/day maintenance therapy. The median times from study entry to retinitis progression were not significantly different between the treatment groups, 96 (range 14 to >176) days and 140 (range 16 to >233) days, respectively.

In study ACTG 129/FGCRT SOCA study 107 patients with newly diagnosed CMV retinitis were randomized to treatment with Foscarnet sodium (induction: 60 mg/kg TID for 2 weeks; maintenance: 90 mg/kg QD) and 127 were randomized to treatment with ganciclovir (induction: 5 mg/kg BID; maintenance: 5 mg/kg QD). The median time to progression on the two drugs was similar (Fos=59 and Gcv=56 days).

Relapsed CMV Retinitis: The CMV Retinitis Retreatment Trial (ACTG 228/SOCA CRRT) was a randomized, open-label comparison of Foscarnet sodium or ganciclovir monotherapy to the combination of both drugs for the treatment of persistently active or relapsed CMV retinitis in patients with AIDS. Subjects were randomized to one of the three treatments: Foscarnet sodium 90 mg/kg BID induction followed by 120 mg/kg QD maintenance (Fos); ganciclovir 5 mg/kg BID induction followed by 10 mg/kg QD maintenance (Gcv); or the combination of the two drugs, consisting of continuation of the subject’s current therapy and induction dosing of the other drug (as above), followed by maintenance with Foscarnet sodium 90 mg/kg QD plus ganciclovir 5 mg/kg QD (Cmb). Assessment of retinitis progression was performed by masked evaluation of retinal photographs. The median times to retinitis progression or death were 39 days for the Foscarnet sodium group, 61 days for the ganciclovir group and 105 days for the combination group. For the alternative endpoint of retinitis progression (censoring on death), the median times were 39 days for Foscarnet sodium group, 61 days for the ganciclovir group and 132 days for the combination group. Due to censoring on death, the latter analysis may overestimate the treatment effect. Treatment modification due to toxicity were more common in the combination group than in the Foscarnet sodium or ganciclovir monotherapy groups (see ADVERSE REACTIONS section).

Mucocutaneous Acyclovir-Resistant HSV Infections: In a controlled trial, patients with AIDS and mucocutaneous, acyclovir-resistant HSV infection were randomized to either Foscarnet sodium (N=8) at a dose of 40 mg/kg TID or vidarabine (N=6) at a dose of 15 mg/kg per day. Eleven patients were non-randomly assigned to receive treatment with Foscarnet sodium because of prior intolerance to vidarabine. Lesions in the eight patients randomized to Foscarnet sodium healed after 11 to 25 days; seven of the 11 patients non-randomly treated with Foscarnet sodium healed their lesions in 10 to 30 days. Vidarabine was discontinued because of intolerance (N=4) or poor therapeutic response (N=2). In a second trial, forty AIDS patients and three bone marrow transplant recipients with mucocutaneous, acyclovir-resistant HSV infections were randomized to receive Foscarnet sodium at a dose of either 40 mg/kg BID or 40 mg/kg TID. Fifteen of the 43 patients had healing of their lesions in 11 to 72 days with no difference in response between the two treatment groups.

Indications and Usage for Foscarnet

CMV Retinitis: Foscarnet sodium injection is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). Combination therapy with Foscarnet sodium and ganciclovir is indicated for patients who have relapsed after monotherapy with either drug. SAFETY AND EFFICACY OF Foscarnet SODIUM HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER CMV INFECTIONS (e.g., PNEUMONITIS, GASTROENTERITIS); CONGENITAL OR NEONATAL CMV DISEASE; OR NON-IMMUNOCOMPROMISED INDIVIDUALS.

Mucocutaneous Acyclovir-Resistant HSV Infections: Foscarnet sodium injection is indicated for the treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients. SAFETY AND EFFICACY OF Foscarnet SODIUM HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER HSV INFECTIONS (e.g., RETINITIS, ENCEPHALITIS); CONGENITAL OR NEONATAL HSV DISEASE; OR HSV IN NON-IMMUNOCOMPROMISED INDIVIDUALS.

Contraindications

Foscarnet sodium injection is contraindicated in patients with clinically significant hypersensitivity to Foscarnet sodium.

Warnings

Renal Impairment: THE MAJOR TOXICITY OF Foscarnet SODIUM IS RENAL IMPAIRMENT (see ADVERSE REACTIONS section). Renal impairment is most likely to become clinically evident during the second week of induction therapy, but may occur at any time during Foscarnet sodium treatment. Renal function should be monitored carefully during both induction and maintenance therapy (see PATIENT MONITORING section). Elevations in serum creatinine are usually, but not always, reversible following discontinuation or dose adjustment of Foscarnet sodium injection. Safety and efficacy data for patients with baseline serum creatinine levels greater than 2.8 mg/dL or measured 24-hour creatinine clearances <50 mL/min are limited.

SINCE Foscarnet SODIUM HAS THE POTENTIAL TO CAUSE RENAL IMPAIRMENT, DOSE ADJUSTMENT BASED ON SERUM CREATININE IS NECESSARY. Hydration may reduce the risk of nephrotoxicity. It is recommended that 750 to 1000 mL of 0.9% sodium chloride injection or 5% dextrose solution should be given prior to the first infusion of Foscarnet sodium to establish diuresis. With subsequent infusions, 750 to 1000 mL of hydration fluid should be given with 90 to 120 mg/kg of Foscarnet sodium, and 500 mL with 40 to 60 mg/kg of Foscarnet sodium. Hydration fluid may need to be decreased if clinically warranted.

After the first dose, the hydration fluid should be administered concurrently with each infusion of Foscarnet sodium.

Mineral and Electrolyte Abnormalities: Foscarnet sodium has been associated with changes in serum electrolytes including hypocalcemia, hypophosphatemia, hyperphosphatemia, hypomagnesemia, and hypokalemia (see ADVERSE REACTIONS section). Foscarnet sodium may also be associated with a dose-related decrease in ionized serum calcium which may not be reflected in total serum calcium. This effect is likely to be related to chelation of divalent metal ions such as calcium by Foscarnet. Patients should be advised to report symptoms of low ionized calcium such as perioral tingling, numbness in the extremities and paresthesias. Particular caution and careful management of serum electrolytes is advised in patients with altered calcium or other electrolyte levels before treatment and especially in those with neurologic or cardiac abnormalities and those receiving other drugs known to influence minerals and electrolytes (see PATIENT MONITORING and Drug Interactions sections). Physicians should be prepared to treat these abnormalities and their sequelae such as tetany, seizures or cardiac disturbances. The rate of Foscarnet sodium infusion may also affect the decrease in ionized calcium. Therefore, an infusion pump must be used for administration to prevent rapid intravenous infusion (see DOSAGE AND ADMINISTRATION section). Slowing the infusion rate may decrease or prevent symptoms.

Seizures: Seizures related to mineral and electrolyte abnormalities have been associated with Foscarnet sodium treatment (see WARNING section; Mineral and Electrolyte Abnormalities). Several cases of seizures were associated with death. Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions.

Precautions

General:

Care must be taken to infuse solutions containing Foscarnet sodium only into veins with adequate blood flow to permit rapid dilution and distribution to avoid local irritation (see DOSAGE AND ADMINISTRATION). Local irritation and ulcerations of penile epithelium have been reported in male patients receiving Foscarnet sodium, possibly related to the presence of drug in the urine. Cases of male and female genital irritation/ulceration have been reported in patients receiving Foscarnet. Adequate hydration with close attention to personal hygiene may minimize the occurrence of such events.

Hemopoietic System: Anemia has been reported in 33% of patients receiving Foscarnet sodium in controlled studies. Granulocytopenia has been reported in 17% of patients receiving Foscarnet sodium in controlled studies; however, only 1% (2/189) were terminated from these studies because of neutropenia.

Information for Patients

CMV Retinitis: Patients should be advised that Foscarnet sodium is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during or following treatment. They should be advised to have regular ophthalmologic examinations.

Mucocutaneous Acyclovir-Resistant HSV Infections: Patients should be advised that Foscarnet sodium is not a cure for HSV infections. While complete healing is possible, relapse occurs in most patients. Because relapse may be due to acyclovir-sensitive HSV, sensitivity testing of the viral isolate is advised. In addition, repeated treatment with Foscarnet sodium has led to the development of resistance associated with poorer response. In the case of poor therapeutic response, sensitivity testing of the viral isolate also is advised.

General: Patients should be informed that the major toxicities of Foscarnet are renal impairment, electrolyte disturbances, and seizures, and that dose modifications and possibly discontinuation may be required. The importance of close monitoring while on therapy must be emphasized. Patients should be advised of the importance of reporting to their physicians symptoms of perioral tingling, numbness in the extremities or paresthesias during or after infusion as possible symptoms of electrolyte abnormalities. Should such symptoms occur, the infusion of Foscarnet sodium injection should be stopped, appropriate laboratory samples for assessment of electrolyte concentrations obtained, and a physician consulted before resuming treatment. The rate of infusion must be no more than 1 mg/kg/minute. The potential for real impairment may be minimized by accompanying Foscarnet sodium injection administration with hydration adequate to establish and maintain a diuresis during dosing.

Drug Interactions:

A possible drug interaction of Foscarnet sodium and intravenous pentamidine has been described. Concomitant treatment of four patients in the United Kingdom with Foscarnet sodium and intravenous pentamidine may have caused hypocalcemia; one patient died with severe hypocalcemia. Toxicity associated with concomitant use of aerosolized pentamidine has not been reported.

Since Foscarnet decreases serum concentrations of ionized calcium, concurrent treatment with other drugs known to influence serum calcium concentrations should be used with particular caution. Fatalities have been reported in post-marketing surveillance during concomitant therapy with Foscarnet and pentamidine.

Because of Foscarnet’s tendency to cause renal impairment, the use of Foscarnet sodium should be avoided in combination with potentially nephrotoxic drugs such as aminoglycosides, amphotericin B and intravenous pentamidine (see above) unless the potential benefits outweigh the risks to the patient.

Abnormal renal function has been observed in clinical practice during the use of Foscarnet sodium and ritonavir, or Foscarnet sodium, ritonavir, and saquinavir. (See DOSAGE AND ADMINISTRATION).

Ganciclovir: The pharmacokinetics of Foscarnet and ganciclovir were not altered in 13 patients receiving either concomitant therapy or daily alternating therapy for maintenance of CMV disease.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenicity studies were conducted in rats and mice at oral doses of 500 mg/kg/day and 250 mg/kg/day. Oral bioavailabilty in unfasted rodents is < 20%. No evidence of oncogenicity was reported at plasma drug levels equal to 1/3 and 1/5, respectively, of those in humans (at the maximum recommended human daily dose) as measured by the area-under-the-time/concentration curve (AUC).

Foscarnet sodium showed genotoxic effects in the BALB/3T3 in vitro transformation assay at concentrations greater than 0.5 mcg/mL and an increased frequency of chromosome aberrations in the sister chromatid exchange assay at 1000 mcg/mL. A high dose of Foscarnet (350 mg/kg) caused an increase in micronucleated polychromatic erythrocytes in vivo in mice at doses that produced exposures (area under curve) comparable to that anticipated clinically.

Pregnancy:

Teratogenic Effect

Pregnancy, Category C: Foscarnet sodium did not adversely affect fertility and general reproductive performance in rats. The results of peri- and post-natal studies in rats were also negative. However, these studies used exposures that are inadequate to define the potential for impairment of fertility at human drug exposure levels.

Daily subcutaneous doses up to 75 mg/kg administered to female rats prior to and during mating, during gestation, and 21 days post-partum caused a slight increase (< 5%) in the number of skeletal anomalies compared with the control group. Daily subcutaneous doses up to 75 mg/kg administered to rabbits and 150 mg/kg administered to rats during gestation caused an increase in the frequency of skeletal anomalies/variations. On the basis of estimated drug exposure (as measured by AUC), the 150 mg/kg dose in rats and 75 mg/kg dose in rabbits were approximately one-eighth (rat) and one-third (rabbit) the estimated maximal daily human exposure. These studies are inadequate to define the potential teratogenicity at levels to which women will be exposed.

There are no adequate and well controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, Foscarnet sodium injection should be used during pregnancy only if clearly needed.

Nursing Mothers:

It is not known whether Foscarnet sodium is excreted in human milk; however, in lactating rats administered 75 mg/kg, Foscarnet sodium was excreted in maternal milk at concentrations three times higher than peak maternal blood concentrations.

Pediatric Use:

The safety and effectiveness of Foscarnet sodium in pediatric patients have not been established. Foscarnet sodium is deposited in teeth and bone and deposition is greater in young and growing animals. Foscarnet sodium has been demonstrated to adversely affect development of tooth enamel in mice and rats. The effects of this deposition on skeletal development have not been studied. Since deposition in human bone has also been shown to occur, it is likely that it does so to a greater degree in developing bone in pediatric patients. Administration to pediatric patients should be undertaken only after careful evaluation and only if the potential benefits for treatment outweigh the risks.

Geriatric Use:

No studies of the efficacy or safety of Foscarnet sodium in persons 65 years of age or older have been conducted. However, Foscarnet sodium has been used in patients age 65 years of age and older. The pattern of adverse events seen in these patients is consistent across all age groups. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored. (See DOSAGE AND ADMINISTRATION.)

Adverse Reactions

THE MAJOR TOXICITY OF Foscarnet SODIUM IS RENAL IMPAIRMENT (see WARNINGS section). Approximately 33% of 189 patients with AIDS and CMV retinitis who received Foscarnet sodium (60 mg/kg TID), without adequate hydration, developed significant impairment of renal function (serum creatinine ≥2.0 mg/dL). The incidence of renal impairment in subsequent clinical trials in which 1000 mL of 0.9% sodium chloride injection or 5% dextrose solution was given with each infusion of Foscarnet sodium was 12% (34/280).

Foscarnet sodium has been associated with changes in serum electrolytes including hypocalcemia (15 to 30%), hypophosphatemia (8 to 26%) and hyperphosphatemia (6%), hypomagnesemia (15 to 30%), and hypokalemia (16 to 48%) (see WARNINGS section). The higher percentages were derived from those patients receiving hydration.

Foscarnet sodium treatment was associated with seizures in 18/189 (10%) AIDS patients in the initial five controlled studies (see WARNINGS section). Risk factors associated with seizures included impaired baseline renal function, low total serum calcium, and underlying CNS conditions predisposing the patient to seizures. The rate of seizures did not increase with duration of treatment. Three cases were associated with overdoses of Foscarnet sodium (see OVERDOSAGE section).

In five controlled U.S. clinical trials the most frequently reported adverse events in patients with AIDS and CMV retinitis are shown in Table 5. These figures were calculated without reference to drug relationship or severity.

TABLE 5 − Adverse Events Reported in
Five Controlled US Clinical Trials
	n = 189		n = 189
Fever	65%	Abnormal Renal Function	27%
Nausea	47%	Vomiting	26%
Anemia	33%	Headache	26%
Diarrhea	30%	Seizures	10%

From the same controlled studies, adverse events categorized by investigator as “severe” are shown in Table 6. Although death was specifically attributed to Foscarnet sodium injection in only one case, other complications of Foscarnet sodium (i.e., renal impairment, electrolyte abnormalities, and seizures) may have contributed to patient deaths (see WARNINGS section).

TABLE 6 − Severe Adverse Events
	n = 189
Death	14%
Abnormal Renal Function	14%
Marrow Suppression	10%
Anemia	9%
Seizures	7%

From the five initial U.S. controlled trials of Foscarnet sodium injection, the following list of adverse events has been compiled regardless of causal relationship to Foscarnet sodium. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medications.

Incidence 5% or Greater

Body as a Whole: fever, fatigue, rigors, asthenia, malaise, pain, infection, sepsis, death

Central and Peripheral Nervous System: headache, paresthesia, dizziness, involuntary muscle contractions, hypoesthesia, neuropathy, seizures including grand mal seizures (see WARNINGS)

Gastrointestinal System: anorexia, nausea, diarrhea, vomiting, abdominal pain

Hematologic: anemia, granulocytopenia, leukopenia (see PRECAUTIONS)

Metabolic and Nutritional: mineral and electrolyte imbalances (see WARNINGS) including hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, hyperphosphatemia

Psychiatric: depression, confusion, anxiety

Respiratory System: coughing, dyspnea

Skin and Appendages: rash, increased sweating

Urinary: alterations in renal function including increased serum creatinine, decreased creatinine clearance, and abnormal renal function (see WARNINGS)

Special Senses: vision abnormalities

Incidence between 1% and 5%

Application Site: injection site pain, injection site inflammation

Body as a Whole: back pain, chest pain, edema, influenza-like symptoms, bacterial infections, moniliasis, fungal infections, abscess

Cardiovascular: hypertension, palpitations, ECG abnormalities including sinus tachycardia, first degree AV block and non-specific ST-T segment changes, hypotension, flushing, cerebrovascular disorder (see WARNINGS)

Central and Peripheral Nervous System: tremor, ataxia, dementia, stupor, generalized spasms, sensory disturbances, meningitis, aphasia, abnormal coordination, leg cramps, EEG abnormalities (see WARNINGS)

Gastrointestinal: constipation, dysphagia, dyspepsia, rectal hemorrhage, dry mouth, melena, flatulence, ulcerative stomatitis, pancreatitis

Hematologic: thrombocytopenia, platelet abnormalities, thrombosis, white blood cell abnormalities, lymphadenopathy

Liver and Biliary: abnormal A-G ratio, abnormal hepatic function, increased SGPT, increased SGOT

Metabolic and Nutritional: hyponatremia, decreased weight, increased alkaline phosphatase, increased LDH, increased BUN, acidosis, cachexia, thirst, hypocalcemia (see WARNINGS)

Musculo-Skeletal: arthralgia, myalgia

Neoplasms: lymphoma-like disorder, sarcoma

Psychiatric: insomnia, somnolence, nervousness, amnesia, agitation, aggressive reaction, hallucination

Respiratory System: pneumonia, sinusitis, pharyngitis, rhinitis, respiratory disorders, respiratory insufficiency, pulmonary infiltration, stridor, pneumothorax, hemoptysis, bronchospasm

Skin and Appendages: pruritus, skin ulceration, seborrhea, erythematous rash, maculo-papular rash, skin discoloration

Special Senses: taste perversions, eye abnormalities, eye pain, conjunctivitis

Urinary System: albuminuria, dysuria, polyuria, urethral disorder, urinary retention, urinary tract infections, acute renal failure, nocturia, facial edema

Selected adverse events occurring at a rate of less than 1% in the five initial U.S. controlled clinical trials of Foscarnet sodium include: syndrome of inappropriate antidiuretic hormone secretion, pancytopenia, hematuria, dehydration, hypoproteinemia, increases in amylase and creatinine phosphokinase, cardiac arrest, coma, and other cardiovascular and neurologic complications.

Selected adverse event data from the Foscarnet vs. Ganciclovir CMV Retinitis Trial (FGCRT), performed by the Studies of the Ocular Complications of AIDS (SOCA) Research Group, are shown in Table 7 (see CLINICAL TRIALS section).

TABLE 7 − FGCRT: Selected Adverse Events*
* Values for the treatment groups refer only to patients who completed at least one follow-up visit − i.e., 113 to 119 patients in the ganciclovir group and 93 to 100 in the Foscarnet group. “Events” denotes all events observed and “patients” the number of patients with one or more of the indicated events. † Per person-year at risk ‡ Final frozen SOCA I database dated October 1991.
Event	GANCICLOVIR			Foscarnet
	No. of Events	No. of Patients	Rates†	No. of Events	No. of Patients	Rates†
Absolute neutrophil count decreasing to <0.50 x 109per liter	63	41	1.30	31	17	0.72
Serum creatinine increasing to >260 µmol per liter (>2.9 mg/dL)	6	4	0.12	13	9	0.30
Seizure‡	21	13	0.37	19	13	0.37
Catheterization- related infection	49	27	1.26	51	28	1.46
Hospitalization	209	91	4.74	202	75	5.03

Selected adverse events from ACTG Study 228 (CRRT) comparing combination therapy with Foscarnet sodium injection or ganciclovir monotherapy are shown in Table 8. The most common reason for a treatment change in patients assigned to either Foscarnet sodium injection or ganciclovir was retinitis progression. The most frequent reason for a treatment change in the combination treatment group was toxicity.

TABLE 8 CRRT: Selected Adverse Events
* Pts. = patients with event; † Rate = events/person/year;‡ ANC = absolute neutrophil count
	Foscarnet Sodium N=88			Ganciclovir N=93			Combination N=93
	No. Events	No. Pts.*	Rate†	No. Events	No. Pts.*	Rate†	No. Events	No. Pts.*	Rate†
Anemia (Hgb <70 g/L)	11	7	0.20	9	7	0.14	19	15	0.33
Neutropenia‡
ANC <0.75 x 109 cells/L	86	32	1.53	95	41	1.51	107	51	1.91
ANC <0.50 x 109 cells/L	50	25	0.91	49	28	0.80	50	28	0.85
Thrombocytopenia