Pivya (pivmecillinam HCl)

Dosage of pivmecillinam hydrochloride is expressed in terms of pivmecillinam.

The recommended dosage of pivmecillinam in female patients >=18 years of age with uncomplicated urinary tract infections (uUTI) caused by susceptible isolates of Escherichia coli, Proteus mirabilis and Staphylococcus saprophyticus is 185 mg (1 tablet) orally 3 times daily for 3 to 7 days as clinically indicated.

Administer pivmecillinam orally with or without food.

If a dose of pivmecillinam is missed, instruct patients to take the dose as soon as possible. Do not double the dose to make up for the missed dose.

Store pivmecillinam tablets at 20-25degreesC; excursions permitted between 15-30degreesC. Store and dispense tablets in the unit-dose blisters.

No dosing information is available for this tab.

Pivmecillinam undergoes minimal hepatic metabolism. Mecillinam does not inhibit or induce cytochrome P-450 (CYP) 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Mecillinam is a substrate of the renal transporters organic anion transporter-3 (OAT3), multidrug and extrusion protein-1 (MATE1), multidrug and extrusion protein-2K (MATE2-K). Mecillinam does not inhibit breast cancer resistance protein (BCRP), P-glycoprotein (PgP), MATE1, MATE2-K, organic anion transporter-1 (OAT1), OAT3, organic anion transporting polypeptides-1B1 and 1B3 (OATP1 B1/B3), and organic cation transporter-2 (OCT2) drug transporters. The effect of concomitant use of OAT3, MATE1, or MATE2K inhibitors on the pharmacokinetics of pivmecillinam or mecillinam is unknown.

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

Antibiotics/Fecal Microbiota

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: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

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: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

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: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

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

Penicillins/Methotrexate

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

MECHANISM OF ACTION: Penicillins may compete with the renal tubular secretion of methotrexate.

CLINICAL EFFECTS: The concurrent use of methotrexate and penicillins may result in elevated levels of methotrexate and methotrexate toxicity, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: Patients receiving concurrent therapy with methotrexate and penicillins should be monitored closely for elevated methotrexate levels and methotrexate toxicity. The dose and duration of leucovorin rescue therapy may need to be increased.

DISCUSSION: Elevated methotrexate levels, signs of methotrexate toxicity, and death have been reported following the concurrent use of methotrexate (both low dose and high dose) and penicillin derivatives. In a patient being treated with high-dose methotrexate (8 G/m2), the concurrent use of amoxicillin resulted in a 56% decrease in the clearance of methotrexate and signs of methotrexate toxicity.(1) There are two cases of methotrexate toxicity following the addition of amoxicillin to low-dose methotrexate therapy (7.5 mg-10 mg weekly) for psoriasis. In another case, a patient was found to have a toxic methotrexate level 12 days after her last dose of weekly methotrexate (7.5 mg). The patient had been treated with amoxicillin followed by flucloxacillin.(2) In a case report, dicloxacillin decreased methotrexate clearance 93%.(4) Flucloxacillin was shown to increase the area-under-curve (AUC) of methotrexate by 7.3% in a study in 10 subjects.(5) In a case report, a patient on low-dose methotrexate (5 mg) developed methotrexate pneumonia following the addition of flucloxacillin to his regimen.(5) In a patient being treated with high-dose methotrexate (12 G/m2), the concurrent use of mezlocillin increased the half-life of methotrexate from 10.1 to 27.2 hours.(6) In a case report, a patient developed methotrexate toxicity following the addition of penicillin V potassium to his methotrexate (50 mg weekly).(7) In a case report, penicillin decreased methotrexate clearance 36%.(4) In one report, leucovorin rescue therapy had to be continued for 192 hours following the concurrent use of methotrexate (3 G/m2) and piperacillin. During cycles without concurrent piperacillin, leucovorin rescue therapy was only required for 72 hours.(8) There are two reports of neutropenia and death following the concurrent use of piperacillin and low-dose methotrexate (2.5 mg three times weekly in one patient, 5 mg weekly in another) for psoriasis. One of these patients also received flucloxacillin. (3) In another case report, the concurrent use of piperacillin decreased methotrexate clearance by 67%.(4) In a case report, ticarcillin decreased methotrexate clearance by 60%.(4)

Pivmecillinam/Valproic Acid Derivatives

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

MECHANISM OF ACTION: Pivalic acid is released after hydrolysis from several prodrugs. In humans, formation and urinary excretion of pivaloylcarnitine generated from pivaloyl-CoA is the major route of pivalate elimination.

CLINICAL EFFECTS: Concurrent use of valproic acid or its derivatives and pivmecillinam may increase the risk of low carnitine levels leading to neurologic deficits with or without encephalopathy. Neurologic deficits may present as changes in state of consciousness and/or cognitive function with lethargy and vomiting.(1-3)

PREDISPOSING FACTORS: Patients with low carnitine levels, significant renal impairment, or decreased muscle mass.

PATIENT MANAGEMENT: The US and UK manufacturers of pivmecillinam state that the use of pivmecillinam and valproic acid and its derivatives should be avoided.(1,2) In patients receiving concurrent valproic acid derivatives and pivmecillinam, monitor for unexplained lethargy, vomiting, and/ or changes in mental status. If these symptoms develop, check the patient's carnitine level and administer exogenous carnitine to increase body stores.(3)

DISCUSSION: There are reports of low carnitine levels caused by the long term (> 6 months) use of these agents resulting in neurological deficits caused by the concurrent use of pivalic acid containing products.(3) The patient improved after carnitine supplementation.

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

Selected Cephalosporins & Penicillins/Probenecid

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

MECHANISM OF ACTION: Probenecid impairs the clearance of some cephalosporins and penicillins via inhibition of renal anion transporters in the proximal tubule.(49) It has also been hypothesized that probenecid may affect tissue distribution of cephalosporins.(1-5)

CLINICAL EFFECTS: The concurrent administration of probenecid may result in increased maximum concentration (Cmax), area-under-curve (AUC), and half-life of the cephalosporin or penicillin.(49) While this may improve antibiotic efficacy,(46-48) increased levels may also increase the risk for antibiotic-associated nephrotoxicity.(4)

PREDISPOSING FACTORS: Underlying renal dysfunction may increase the risk for nephrotoxicity.

PATIENT MANAGEMENT: In patients receiving the combination to improve antibiotic efficacy, monitor for antibiotic adverse effects and consider monitoring renal function. In patients receiving probenecid therapy to prevent or treat hyperuricemia, exposure to the antibiotic will be increased. A decrease in antibiotic dose or frequency may be required. The US manufacturer of piperacillin-tazobactam states probenecid should not be coadministered with piperacillin-tazobactam unless the benefit outweighs the risk.(50)

DISCUSSION: Concurrent use of probenecid with a cephalosporin or penicillin may cause an increase in the Cmax, AUC, and an increased elimination half life of the antibiotic.(6-8,49) This may be beneficial or necessary in difficult to treat infections,(46-48) but an increased risk for adverse effects should be expected. Antibiotics not dose adjusted for concurrent use with probenecid may be associated with an increased risk for adverse effects, such as nephrotoxicity. Probenecid administered concurrently with piperacillin-tazobactam prolongs the half-life of piperacillin by 21% and tazobactam by 71%. In a study in 8 healthy males, concurrent administration of probenecid (1 g) with piperacillin (1 g IM) increased piperacillin's Cmax and AUC by 30% and 60%. Renal clearance was reduced by 40%.(51) The cephalosporins affected by probenecid include cefazolin,(9-11) cephacetrile,(12,13) cephaloglycin,(14,15) cephalexin,(16-21) cephradine, (22-23) cefoxitin,(24-28) cefadroxil(29), cefaclor,(23) cefamandole,(30) ceftizoxime,(31,32) cefuroxime,(33,34) cefprozil,(35) cefonicid,(36) cefmetazole,(37) cefmenoxime,(38) and cefditoren.(39) Probenecid has been shown not to affect moxalactam,(4,40,41) ceforanide, (4,42), cefoperazone, ceftazidime(4,34,43) or ceftriaxone.(4)

*Serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to pivmecillinam or other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins).

*Primary or secondary carnitine deficiency resulting from inherited disorders of mitochondrial fatty acid oxidation and carnitine metabolism, and other inborn errors of metabolism (e.g., methylmalonic aciduria, or propionic acidemia).

*Acute porphyria.

• Carnitine deficiency
• Methylmalonic acidemia
• Porphyria
• Propionic acidemia

• Barrett's esophagus
• Clostridioides difficile infection
• Dysphagia
• Esophageal dysmotility
• Esophageal obstruction
• Esophagitis

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

The most common adverse reactions observed in >=2% of the patients receiving pivmecillinam in clinical trials are nausea and diarrhea.

Rare or Very Rare

• Abnormal hepatic function tests
• Acute generalized exanthematous pustulosis
• Angioedema
• Carnitine deficiency
• Clostridioides difficile infection
• DRESS syndrome
• Esophageal ulcer
• Hypersensitivity drug reaction
• Porphyria
• Stevens-johnson syndrome
• Thrombocytopenic disorder
• Toxic epidermal necrolysis

More Frequent

• Diarrhea
• Nausea

Less Frequent

• Genital organ pruritus
• Headache disorder

Rare or Very Rare

• Acute abdominal pain
• Aphthous stomatitis
• Dizziness
• Dyspepsia
• Skin rash
• Urticaria
• Vertigo
• Vomiting
• Vulvovaginal candidiasis

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The safety and effectiveness of pivmecillinam have not been established in pediatric patients.

Symptomatic hypocarnitinemia has been reported in pediatric patients outside the US who were receiving long-term pivmecillinam therapy. Symptoms such as irritability, altered mental status, fatigue, muscle weakness, and vomiting were observed. Pivmecillinam is not recommended when prolonged antibacterial treatment is necessary and is contraindicated in patients with primary or secondary carnitine deficiency.

Newborns exposed to pivmecillinam in utero prior to delivery may have a false positive newborn screening test for isovaleric acidemia. Prompt follow-up of a positive result for isovaleric acidemia is recommended.

Published observational studies in pregnant women who were exposed to pivmecillinam during the first trimester of pregnancy did not indicate an increased risk of major birth defects compared to pregnant women exposed to other antibacterial drugs. There are limited studies evaluating the risk of miscarriage and other adverse maternal or fetal outcomes with the use of pivmecillinam during pregnancy. In animal reproductive studies, reduced ossification was observed in the offspring of rats administered pivmecillinam during organogenesis at doses approximately 10.2-fold higher than the recommended maximum daily human dose; there was no evidence of other embryofetal toxicity.

No dosage adjustment of pivmecillinam is required in pregnant women.

Treatment of a pregnant individual with pivmecillinam prior to delivery may cause a false positive test for isovaleric acidemia in the newborn.

Mecillinam is present in animal milk; when a drug is present in animal milk, it is likely to be present in human milk. Adverse reactions including rash and diarrhea have been reported in breastfed infants exposed to mecillinam. There are no data on the effects of mecillinam on milk production.

Consider the developmental and health benefits of breastfeeding along with the mother`s clinical need for pivmecillinam and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

The manufacturer states that the available safety information does not suggest a need for dosage adjustments in geriatric patients.

In clinical trials evaluating safety and efficacy of pivmecillinam, approximately 13-14% of patients were 65 years of age and older and 3% were 75 years of age and older.

The pharmacokinetics of mecillinam in geriatric patients have not been evaluated; however, pivmecillinam is known to be substantially excreted by the kidneys, and geriatric patients are more likely to have reduced renal function. The clinical significance of these changes on efficacy or safety is unknown. The available safety information does not suggest a need for dosage adjustment.