Pivya Drug Information

Recommended Dosage

The recommended dosage of PIVYA is one 185 mg tablet orally 3 times a day for 3 to 7 days as clinically indicated. Administer PIVYA with or without food . PIVYA (pivmecillinam) is a prodrug of mecillinam (the active antibacterial agent) .

Recommendations Regarding Missed Dose(s)

If a dose of PIVYA is missed, instruct patients to take the dose as soon as possible. Do notdouble the dose to make up for the missed dose.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of PIVYA was evaluated in 579 adult female patients with uUTI who received PIVYA at a dose of 185 mg three times daily, or at higher daily doses (not approved for PIVYA) for 3 to 10 days in a placebo controlled trial (Trial 1, N=282), an active controlled trial (Trial 2, N=213) and an open label trial (Trial 3, N=84). The majority of patients were White women between 18 and 91 years of age. No serious adverse reactions were reported in patients treated with PIVYA in the trials.

In Trial 1, the most common adverse reactions observed in ≥2% of the patients receiving PIVYA included nausea (4.3%) and diarrhea (2.1%). In Trial 2 and Trial 3, the most common adverse reaction occurring in ≥1% of patients receiving PIVYA was nausea with an incidence of 1.4% in Trial 2 and 3.6% in Trial 3. Table 1 lists the most frequently reported adverse reactions occurring in ≥1% of patients receiving PIVYA in Trial 1. Table 1 Adverse Reactions Occurring in ≥1% of Patients Receiving PIVYA in Trial 1 Adverse Reactions (AR) PIVYA* N=282 n (%) Placebo N=288 n (%) Nausea 12 6 Diarrhea 6 2 Vulvovaginal candidiasis 5 0 Genital pruritus 5 4 Headache 4 1 *PIVYA 185 mg three times per day for 7 days Selected adverse reactions occurring in ≤1% of patients who received PIVYA in the clinical trials were vomiting, rash, dyspepsia, and abdominal pain.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of pivmecillinam outside of the United States. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorder: Thrombocytopenia Ear and labyrinth disorder: Vertigo Gastrointestinal disorders: Esophageal ulcer, esophagitis, mouth ulceration Hepatobiliary disorders: Hepatic function abnormal Immune system disorders: Anaphylactic reaction, Angioedema Infections and infestations: Clostridioides difficile- associated diarrhea Metabolism and nutrition disorders: Carnitine decreased Nervous system disorders: Dizziness Skin and subcutaneous tissue disorders : Urticaria, pruritus, Severe Cutaneous Adverse Reactions (SCAR) including Acute Generalized Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

Other Pivalate-Generating Drugs

Avoid concurrent treatment with valproic acid, valproate, or other pivalate-generating drugs. If concomitant use with PIVYA is necessary, counsel patients to monitor adverse reactions associated with carnitine depletion (e.g., hypoglycemia, muscle aches, fatigue, and confusion). Pivmecillinam is a pivalate-generating prodrug . Pivalate can be activated to a coenzyme-A thioester in cells which is further converted to pivaloylcarnitine and excreted in urine. Pivalate elimination associated with concomitant use of pivmecillinam with other pivalate-generating drugs decreases carnitine concentrations in plasma which may increase the risk of carnitine depletion-associated adverse reactions .

Methotrexate Clearance of methotrexate from the body can be reduced by concurrent

use of drugs in the penicillin class, including PIVYA. Where possible, consider alternative therapy.

Drug Interference with Newborn Screening Test Treatment of a pregnant individual with

PIVYA prior to delivery may cause a false positive test for isovaleric acidemia in the newborn as part of newborn screening. Prompt follow-up of a positive newborn screening result for isovaleric acidemia is recommended.

Pregnancy Risk Summary Published observational studies on PIVYA use during the first trimester do not indicate an increased risk of major birth defects ( see Data ). There are limited studies on PIVYA use during pregnancy that evaluate the risk of miscarriage and other adverse maternal or fetal outcomes. These studies have methodological limitations hindering interpretation. No dose adjustment is required in pregnant women (see Clinical Considerations). Developmental toxicity studies with pivmecillinam or mecillinam administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses approximately 3.4 or 7.9 times (rats) or 5.1 or 3.9 times (mice) higher than given to patients receiving the maximum recommended daily dose.

Evidence of slight fetotoxicity (reduced ossification) was seen in offspring of rats that were given pivmecillinam during organogenesis at a dose approximately 10.2-fold higher than the maximum recommended daily human dose (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Interference with Newborn Screening Test Treatment of a pregnant individual with PIVYA prior to delivery may cause a false positive test for isovaleric acidemia in the newborn as part of newborn screening. Dose Adjustments During Pregnancy and the Postpartum Period No dosage adjustment is recommended for pregnant females (see Data). Data Human data Two cohort studies in 42,223 pregnant women who were exposed to PIVYA during the first trimester did not observe an increased risk of major birth defects when compared to 50,099 pregnant women exposed to other antibacterial drugs. These two studies were limited by potential exposure misclassification.

No clinically significant differences in mecillinam C max and AUC were observed in pregnant adult women (10 to 32 weeks gestation) administered PIVYA 185 mg orally in a published study. Animal data Pivmecillinam administered during the period of organogenesis (gestation days 6-15) had no adverse effects on embryofetal development in rats or mice at oral doses up to 194 mg/kg/day in rats and 582 mg/kg/day in mice. These doses are approximately 3.4-fold and 5.1-fold higher than the maximum recommended daily human dose based on body surface area, respectively.

There was a skeletal variation (reduced ossification of sternebrae, possibly indicating slight fetotoxicity) in offspring of rats treated at 582 mg/kg/day (approximately 10.2-fold higher than the maximum recommended daily human dose based on body surface area). Mecillinam did not cause adverse effects on embryofetal development in rats and mice when administered by subcutaneous injection at doses up to 450 mg/kg/day (approximately 7.9-fold and 3.9-fold higher than the maximum recommended daily human dose based on body surface area, respectively). In pre- and postnatal studies in rats where maternal animals were dosed beginning during gestation (Day 15) and continuing throughout the weaning period, neither pivmecillinam nor mecillinam had adverse effects on the maternal animals or on the survival and development of the offspring. Pivmecillinam was given orally at doses up to 582 mg/kg/day and mecillinam was given subcutaneously at doses up to 450 mg/kg/day (approximately 10.2-fold and 7.9-fold higher than the maximum recommended daily human dose of PIVYA, based on body surface area, respectively).

Pediatric Use The safety and effectiveness of PIVYA have not been established in pediatric patients. Carnitine Depletion Symptomatic hypocarnitinemia has been reported in pediatric patients outside the United States on long term pivmecillinam therapy. In these cases, irritability, altered mental status, fatigue, muscle weakness, and vomiting have been observed.

PIVYA is not recommended when prolonged antibacterial treatment is necessary. PIVYA is contraindicated in patients with primary or secondary carnitine deficiency . Interference with Newborn Screening Test Newborns exposed to PIVYA in utero prior to delivery may have a false positive newborn screening test for isovaleric acidemia. Prompt follow-up of a positive newborn screening result for isovaleric acidemia is recommended .

Serious Hypersensitivity Reactions

PIVYA is contraindicated in patients who have experienced a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to PIVYA or other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins).

Carnitine Deficiency

PIVYA is contraindicated in patients with 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

PIVYA is contraindicated in patients suffering from porphyria as pivmecillinam has been associated with acute attacks of porphyria .