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Important Safety Info

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions

Serious hypersensitivity reactions (anaphylaxis) have been reported in patients treated with PIVYA [see Adverse Reactions ( 6.1)] . These reactions are more likely to occur in individuals with a history of penicillin, cephalosporin, or carbapenem hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with PIVYA, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, carbapenems, and other beta-lactams because cross-hypersensitivity has been reported. PIVYA is contraindicated in patients who have experienced a serious hypersensitivity reaction. If an allergic reaction occurs, discontinue PIVYA and institute appropriate therapy.

Severe Cutaneous Adverse Reactions

Severe Cutaneous Adverse Reactions (SCAR) including Acute Generalized Exanthematous Pustulosis (AGEP), Drug Reactions with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported with PIVYA. Monitor patients closely and discontinue PIVYA at the first signs or symptoms of SCAR or other signs of hypersensitivity.

Carnitine Depletion

Clinical manifestations of carnitine depletion may occur with pivalate-containing compounds, including PIVYA. Symptoms of carnitine depletion include hypoglycemia, muscle aches, fatigue, and confusion. PIVYA is contraindicated in patients with primary or secondary carnitine deficiency due to inherited metabolic disorders known to cause carnitine depletion. No clinical effects of decreased carnitine have been associated with short-term treatment of PIVYA. Clinically significant hypocarnitinemia has been observed in patients receiving long term treatment with pivmecillinam. PIVYA is not recommended when prolonged antibacterial treatment is necessary. The effects on carnitine concentrations of repeated short-term courses of PIVYA are not known. In patients at risk for reductions in serum carnitine (e.g., patients with significant renal impairment or decreased muscle mass consider alternative antibacterial therapies. Avoid concurrent treatment with valproic acid, valproate or other pivalate-generating drugs due to increased risk of carnitine depletion.

Acute Porphyria

PIVYA is contraindicated in patients suffering from porphyria as pivmecillinam has been associated with acute attacks of porphyria. These episodes may be life-threatening, and include symptoms and signs such as anxiety, confusion, limb or abdominal pain, hyponatremia, seizures, and muscle weakness.

Clostridioides difficile-Associated Diarrhea

Clostridioidesdifficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including PIVYA, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B that contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplement, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development of Drug-Resistant Bacteria

Prescribing PIVYA in the absence of a proven or strongly suspected bacterial infection or for prophylaxis is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria .

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.

ADVERSE REACTIONS

The following clinically significant adverse reactions are described in greater detail in the Warnings and Precautions section of labeling:The following clinically significant adverse reactions are described in greater detail in the Warnings and Precautions section of labeling:

Hypersensitivity Reactions

Severe Cutaneous Adverse Reactions

Carnitine Depletion

Acute Porphyria

Clostridioides difficile-Associated Diarrhea

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 (4.3)	6 (2.1)
Diarrhea	6 (2.1)	2 (0.7)
Vulvovaginal candidiasis	5 (1.8)	0
Genital pruritus	5 (1.8)	4 (1.4)
Headache	4 (1.4)	1 (0.3)

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)

ADVERSE REACTIONS

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

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

Published observational studies on PIVYA use during the first trimester do not indicate an increased risk of major birth defects. 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. 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. 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

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).

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

There are insufficient data to exclude the presence of mecillinam in human milk. Mecillinam is present in animal milk. When a drug is present in animal milk, it is likely to be present in human milk. There are pharmacovigilance reports of adverse reactions with mecillinam exposure in breastfed infants, including rash and diarrhea. There are no data on the effects of mecillinam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother`s clinical need for PIVYA and any potential adverse effects on the breastfed child from PIVYA or from the underlying maternal condition.

Data

In a study of lactating cows given 8 mg/kg mecillinam IV, the concentration in milk was 0.1 and 0.7 μg/mL at 2 and 6 hours, respectively, and the total excretion in milk over the first 6 hours was 0.03% of the injected dose. The concentration of mecillinam in animal milk does not necessarily predict the concentration of drug in human milk.

Pediatric Use

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

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Eligibility Requirements

CONTRAINDICATIONS

Serious Hypersensitivity Reactions

Carnitine Deficiency

Acute Porphyria

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions

Severe Cutaneous Adverse Reactions

Carnitine Depletion

Acute Porphyria

Clostridioides difficile-Associated Diarrhea

Development of Drug-Resistant Bacteria

Interference with Newborn Screening Test

ADVERSE REACTIONS

Hypersensitivity Reactions

Severe Cutaneous Adverse Reactions

Carnitine Depletion

Acute Porphyria

Clostridioides difficile-Associated Diarrhea

Clinical Trials Experience

Post-Marketing Experience

ADVERSE REACTIONS

Other Pivalate-Generating Drugs

Methotrexate

Drug Interference with Newborn Screening Test

USE IN SPECIFIC POPULATIONS

Pregnancy

USE IN SPECIFIC POPULATIONS

Pregnancy

Pediatric Use