Uroqid-Acid No.2 (methenamine mandelate/sodium phosphate,monobasic)

Methenamine is commercially available as methenamine hippurate and methenamine mandelate; dosage is expressed in terms of the salt.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Methenamine/Sulfonamides

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Methenamine is hydrolyzed to formaldehyde in acidic urine. Sulfonamides may form an insoluble precipitate with formaldehyde in the urine.(1,2)

CLINICAL EFFECTS: The concurrent administration of methenamine and sulfamethizole or sulfathiazole is likely to form a precipitate in the urine.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Methenamine should not be administered to patients receiving sulfonamides.(1-3)

DISCUSSION: Methenamine is hydrolyzed to formaldehyde in acidic urine. An in vitro study showed that addition of methenamine and mandelic acid to saturated solutions of sulfamethizole at pH 5.0 and 6.0 produced a precipitate in one hour.(4)

Methenamine/Urinary Alkalinizers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Urinary alkalinizers may elevate urinary ph preventing the conversion of methenamine to formaldehyde and mandelic acid.(1)

CLINICAL EFFECTS: Concurrent administration may result in alkalinization of the urine causing methenamine to be less effective.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian and UK manufacturers of methenamine state that concurrent use with agents that make urine alkaline or urine alkalinizing agents should be avoided.(2,3) Patients receiving concurrent therapy should be monitored for urinary ph and any worsening symptoms of their infection, including dysuria, flank pain, or fever.(1)

DISCUSSION: Administration of urinary alkalinizers may result in alkalinization of the urine resulting in therapeutic failure of methenamine. Formaldehyde is released by acid hydrolysis from methenamine resulting in bactericidal concentrations at urinary ph 5.0 to 5.5. Above urinary ph 6.0 there is insufficient quantities of formaldehyde and methenamine released to achieve a therapeutic response.(1) An in vitro study showed that methenamine efficacy is achieved when the urine pH is less than 5.7 to 5.85.(4)

Oral Phosphates; Active Vitamin D Analogs/Burosumab

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both burosumab and phosphates or vitamin D may increase serum phosphate levels. This combination may lead to greater increases in serum phosphate than anticipated.

CLINICAL EFFECTS: The combination of burosumab with oral phosphates or active vitamin D analogs may result in hyperphosphatemia and may increase the risk of nephrocalcinosis.(1)

PREDISPOSING FACTORS: Patients with renal impairment have alterations in mineral metabolism that may increase the risk of hyperphosphatemia.(1)

PATIENT MANAGEMENT: The concomitant use of burosumab with oral phosphates or active vitamin D analogs is contraindicated. Discontinue oral phosphate and/or active vitamin D analogs one week before starting burosumab.(1)

DISCUSSION: Burosumab restores dysfunctional renal phosphate reabsorption and renal production of 1,25-dihydroxyvitamin D to treat X-linked hypophosphatemia. Additional oral phosphates and/or active vitamin D analogs may raise serum phosphate higher than anticipated.

Urinary Alkalinizers/Methenamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Urinary alkalinizers may elevate urinary ph preventing the conversion of methenamine to formaldehyde and mandelic acid.(1)

CLINICAL EFFECTS: Concurrent administration may result in alkalinization of the urine causing methenamine to be less effective.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Australian and UK manufacturers of methenamine state that concurrent use with agents that make urine alkaline or urine alkalinizing agents should be avoided.(2,3) Patients receiving concurrent therapy should be monitored for urinary ph and any worsening symptoms of their infection, including dysuria, flank pain, or fever.(1)

DISCUSSION: Administration of urinary alkalinizers may result in alkalinization of the urine resulting in therapeutic failure of methenamine. Formaldehyde is released by acid hydrolysis from methenamine resulting in bactericidal concentrations at urinary ph 5.0 to 5.5. Above urinary ph 6.0 there is insufficient quantities of formaldehyde and methenamine released to achieve a therapeutic response.(1) An in vitro study showed that methenamine efficacy is achieved when the urine pH is less than 5.7 to 5.85.(4)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Oral Phosphate Supplements; Urinary Ph Modifiers/Alum;Ca;Mag

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Medications containing significant amounts of aluminum, calcium, or magnesium may bind to the phosphate and prevent its absorption.(1)

CLINICAL EFFECTS: Concurrent use of medications containing significant amounts of aluminum, calcium, or magnesium may result in decreased effectiveness of phosphate supplements and urinary pH modifiers high in phosphate.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving phosphate supplements or urinary pH modifiers high in phosphate should be instructed to avoid medications containing aluminum, calcium, or magnesium.(1) If concurrent use cannot be avoided, separate the administration of phosphate containing products by as much time as possible from medications containing aluminum, calcium, or magnesium. Some phosphate laxative products used as phosphate supplements may contain sufficient quantities of phosphate to interact as well.

DISCUSSION: The manufacturer of K-Phos states that products containing aluminum, calcium, or magnesium may bind to the phosphate and prevent its absorption. Therefore, patients receiving phosphate supplements and urinary pH modifiers high in phosphate should be instructed to avoid products containing aluminum, calcium, or magnesium.(1)

Phosphate Supplements;Urine Ph Modifiers/Phosphate Reducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lanthanum and sevelamer bind to phosphate.(1-2) Tenapanor is a sodium/hydrogen exchanger 3 (NHE3) inhibitor.(3) All three agents are used to lower phosphate absorption in the body.(1-3)

CLINICAL EFFECTS: Concurrent use of phosphate supplements or urinary pH modifiers high in phosphate with agents that reduce serum phosphorus may decrease the effectiveness of both agents.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should normally not receive phosphate supplements or urinary pH modifiers high in phosphate concurrently with agents that reduce serum phosphorus.

DISCUSSION: Lanthanum, sevelamer, and tenapanor are indicated to control phosphorus levels. Consider discontinuing or holding phosphate supplements and urinary pH modifiers high in phosphate in patients receiving these agents.

Serum Phosphate Level-Altering Drugs/Erdafitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Medications that alter serum phosphate may interfere with interpretation of phosphate levels that are needed to determine initial erdafitinib dose.(1)

CLINICAL EFFECTS: Serum phosphate levels that are elevated by concomitant medications may result in an inappropriately low dose and decreased effectiveness of erdafitinib. Serum phosphate levels that are decreased by concomitant medications may result in an inappropriately high dose and increased toxicity from erdafitinib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of erdafitinib states that agents that alter serum phosphate levels should be avoided before the initial dose increase period for erdafitinib based on serum phosphate levels (days 14 to 21).(1)

DISCUSSION: Concomitant administration of serum phosphate level-altering agents during the initial dose increase period of erdafitinib based on serum phosphate levels (days 14 to 21) may interfere with serum phospate levels and lead to incorrect dosing of erdafitinib.(1) Agents that may alter serum phosphate levels linked to this monograph include: aluminum carbonate, aluminum hydroxide, calcium acetate, calcium carbonate, calcium citrate, cod liver oil, ferric citrate, lanthanum, magnesium carbonate, magnesium hydroxide, potassium phosphate, sevelamer, sodium phosphate, sucroferric oxyhydroxide, tenapanor, and vitamin D.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Urinary Alkalinizers/Memantine; Amantadine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Memantine and amantadine elimination is impaired by urinary alkalinization.(1,2)

CLINICAL EFFECTS: Potentiation of memantine or amantadine effects may be observed.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patient for adverse reactions such as dizziness, headache, or confusion if a urinary alkalinizer is required. The memantine or amantadine dose may need to be adjusted when a urinary alkalinizer is started or stopped.(1,2)

DISCUSSION: The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Urine alkalinization may lead to an accumulation of memantine with a possible increase in adverse effects. Urine pH is also altered by diet and clinical state of the patient (e.g., renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions.(1) A study in rats showed that concomitant administration of sodium bicarbonate with amantadine caused a decrease in amantadine renal clearance (1.16 vs. 0.76). Amantadine's area-under-the-curve (AUC) was increased approximately 78%.(3) A study in 12 healthy subjects showed that plasma concentrations of memantine are dependent on urine pH. Alkaline urine pH caused a 79% reduction in renal clearance.(4)

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• Hypernatremia
• Hyperphosphatemia
• Hypocalcemia
• Kidney disease with reduction in glomerular filtration rate (GFr)

• Chronic heart failure
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Dehydration
• Disease of liver
• Edema

• Hepatic cirrhosis
• Kidney disease with likely reduction in glomerular filtration rate (GFr)
• Severe hepatic disease

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Less Frequent

• Skin rash

Rare or Very Rare

• Acute renal failure
• Body fluid retention
• Cardiac arrhythmia
• Cardiac arrhythmia
• Dyspnea
• Hematuria
• Hyperkalemia
• Hypernatremia
• Hypernatremia
• Hyperphosphatemia
• Hyperphosphatemia
• Hypocalcemia
• Hypocalcemic tetany
• Hypovolemia
• Ischemic colitis
• Nephrocalcinosis
• Nephrocalcinosis
• Oliguria
• Renal failure
• Renal failure
• Seizure disorder
• Seizure disorder
• Unconsciousness

Less Frequent

• Abdominal pain with cramps
• Diarrhea
• Diarrhea
• Dyspepsia
• Nausea
• Nausea
• Nausea
• Vomiting
• Vomiting

Rare or Very Rare

• Acute abdominal pain
• Arthralgia
• Bone pain
• Cramps
• Dizziness
• Dysuria
• General weakness
• Headache disorder
• Oral paresthesia
• Paresthesia
• Peripheral edema
• Polydipsia
• Pruritus of skin
• Weight gain

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Reproduction studies in rats and rabbits using methenamine hippurate have not revealed evidence of harm to the fetus. A slight increase in the stillborn rate and slight impairment of weight gain and survival of live-born offspring was reported in a study in pregnant dogs using oral methenamine in dosages equivalent to the human dosage. There are no adequate and well-controlled studies to date using methenamine hippurate or methenamine mandelate in pregnant women, and the drugs should be used during pregnancy only when clearly needed.

Although safe use of methenamine or its salts during pregnancy has not been definitely established, the drugs have been used in pregnant women without adverse effects to the fetus. One manufacturer of methenamine hippurate states that safety during the last trimester is suggested, but not definitely proven.

The effects of methenamine during labor and delivery are unknown and there are no recognized uses for the drug during labor or delivery.

Because methenamine is distributed into milk and because of the potential for serious adverse effects in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

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