PIVYA (pivmecillinam hcl)

There are 4 contraindications. Absolute contraindication.

Contraindication List
Carnitine deficiency
Methylmalonic acidemia
Porphyria
Propionic acidemia

There are 6 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

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

There are 1 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Kidney disease with reduction in glomerular filtration rate (GFr)

There are 12 severe adverse reactions.

More Frequent	Less Frequent
None.	None.

Rare/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

There are 13 less severe adverse reactions.

More Frequent	Less Frequent
Diarrhea Nausea	Genital organ pruritus Headache disorder

Rare/Very Rare
Acute abdominal pain Aphthous stomatitis Dizziness Dyspepsia Skin rash Urticaria Vertigo Vomiting Vulvovaginal candidiasis

Published observational studies on pivmecillinam use during the first trimester do not indicate an increased risk of major birth defects. There are limited studies on pivmecillinam 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. Treatment of a pregnant individual with pivmecillinam prior to delivery may cause a false positive test for isovaleric acidemia in the newborn as part of newborn screening.

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 pivmecillinam and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

In a study of lactating cows given 8 mg/kg mecillinam IV, the concentration in milk was 0.1 and 0.7 microg/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.

Of the total number of pivmecillinam-treated patients in the clinical trials evaluated for safety, 80/579 (14%) were 65 years of age and older, and 48/369 (13%) were 65 years of age and older in the pivmecillinam-treated patients evaluated for efficacy. A total of 19/579 (3%) of the pivmecillinam-treated patients evaluated for safety were 75 years of age and older and 12/369 (3%) were 75 years of age and older in the pivmecillinam-treated patients evaluated for efficacy. No overall differences in safety or effectiveness of pivmecillinam have been observed between patients 65 years of age and older and younger adult patients.

Mecillinam pharmacokinetics data from geriatric patients are not available. pivmecillinam is known to be substantially excreted by the kidneys, and geriatric patients are anticipated 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.