HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------- WARNINGS AND PRECAUTIONS -----------------------

These highlights do not include all the information needed to use • Hypersensitivity Reactions: Serious hypersensitivity reactions including
PIVYA safely and effectively. See full prescribing information for anaphylaxis have been reported in patients treated with PIVYA. If
PIVYA. hypersensitivity reactions occur, discontinue treatment with PIVYA and
PIVYA (pivmecillinam) tablets, for oral use institute appropriate therapy. (5.1)
Initial U.S. Approval: 2024 • Severe Cutaneous Adverse Reactions (SCAR): Acute Generalized
Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia
--------------------------- INDICATIONS AND USAGE---------------------------- and Systemic Symptoms (DRESS), Steven-Johnson Syndrome (SJS) and
PIVYA is a penicillin class antibacterial indicated for the treatment of female Toxic Epidermal Necrolysis (TEN) have been reported with PIVYA.
patients 18 years of age and older with uncomplicated urinary tract infections Monitor patients closely and discontinue PIVYA at the first signs or
(uUTI) caused by susceptible isolates of Escherichia coli, Proteus mirabilis symptoms of SCAR or other signs of hypersensitivity. (5.2)
and Staphylococcus saprophyticus. (1.1) • Carnitine Depletion: Clinically significant hypocarnitinemia has been
observed in patients at risk for reductions in serum carnitine. In patients
To reduce the development of drug-resistant bacteria and maintain the with significant renal impairment or decreased muscle mass and those
effectiveness of PIVYA and other antibacterial drugs, PIVYA should be used patients requiring long term antimicrobial treatment, consider alternative
only to treat or prevent infections that are proven or strongly suspected to be antibacterial therapies. PIVYA is not recommended when prolonged
caused by bacteria. (1.2) antibacterial treatment is necessary. Avoid concurrent treatment with
-----------------------DOSAGE AND ADMINISTRATION ----------------------- valproic acid, valproate or other pivalate-generating drugs due to
• The recommended dosage of PIVYA is one 185 mg tablet orally 3 times increased risk of carnitine depletion. (5.3)
a day for 3 to 7 days as clinically indicated. (2.1) • Clostridioides difficile-Associated Diarrhea (CDAD): This has been
• Administer PIVYA with or without food. (2.1) reported for nearly all systemic antibacterial agents, including PIVYA.
--------------------- DOSAGE FORMS AND STRENGTHS---------------------- Evaluate if diarrhea occurs (5.5)
Tablets: 185 mg pivmecillinam. (3) • Interference with Newborn Screening Test: Treatment of a pregnant
------------------------------ CONTRAINDICATIONS ------------------------------ individual with PIVYA prior to delivery may cause a false positive test
• Serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson for isovaleric acidemia in the newborn as part of newborn screening.
syndrome) to PIVYA or to other beta-lactam antibacterial drugs (e.g., Prompt follow-up of a positive newborn screening result for isovaleric
penicillins and cephalosporins). (4.1) acidemia is recommended. (5.7)
• Primary or secondary carnitine deficiency resulting from inherited ------------------------------ ADVERSE REACTIONS ------------------------------
disorders of mitochondrial fatty acid oxidation and carnitine metabolism, The most common adverse reactions observed in ≥2% of the patients
and other inborn errors of metabolism (e.g., methylmalonic aciduria, or receiving PIVYA in clinical trials are nausea and diarrhea. (6.1)
propionic acidemia). (4.2) To report SUSPECTED ADVERSE REACTIONS, contact UTILITY
• Acute porphyria. (4.3) therapeutics Ltd at 1-888-353-3180 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION

Revised: 4/2024

Reference ID: 5369700

 FULL PRESCRIBING INFORMATION: 7.2 Methotrexate
CONTENTS* 7.3 Drug Interference with Newborn Screening
1 INDICATIONS AND USAGE
Test
1.1 Uncomplicated Urinary Tract Infections
8 USE IN SPECIFIC POPULATIONS
(uUTI)
8.1 Pregnancy
1.2 Usage
8.2 Lactation
2 DOSAGE AND ADMINISTRATION
8.4 Pediatric Use
2.1 Recommended Dosage
8.5 Geriatric Use
2.2 Recommendations Regarding Missed
8.6 Renal Impairment
Dose(s)
11 DESCRIPTION
3 DOSAGE FORMS AND STRENGTHS
12 CLINICAL PHARMACOLOGY
4 CONTRAINDICATIONS
12.1 Mechanism of Action
4.1 Serious Hypersensitivity Reactions
12.2 Pharmacodynamics
4.2 Carnitine Deficiency
12.3 Pharmacokinetics
4.3 Acute Porphyria
12.4 Microbiology
5 WARNINGS AND PRECAUTIONS
13 NONCLINICAL TOXICOLOGY
5.1 Hypersensitivity Reactions
13.1 Carcinogenesis, Mutagenesis, and
5.2 Severe Cutaneous Adverse Reactions
Impairment of Fertility
5.3 Carnitine Depletion
14 CLINICAL STUDIES
5.4 Acute Porphyria
16 HOW SUPPLIED/STORAGE AND
5.5 Clostridioides difficile-Associated Diarrhea
HANDLING
5.6 Development of Drug-Resistant Bacteria
16.1 How Supplied
5.7 Interference with Newborn Screening Test
16.2 Storage and Handling
6 ADVERSE REACTIONS
17 PATIENT COUNSELING INFORMATION
6.1 Clinical Trials Experience
6.2 Post-Marketing Experience
*Sections or subsections omitted from the full
7 DRUG INTERACTIONS prescribing information are not listed.
7.1 Other Pivalate-Generating Drugs

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 FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE

1.1 Uncomplicated Urinary Tract Infections

PIVYA is indicated for the treatment of female patients 18 years of age and older with
uncomplicated urinary tract infections (uUTI) caused by susceptible isolates of Escherichia coli
(E. coli), Proteus mirabilis, and Staphylococcus saprophyticus.

1.2 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of PIVYA
and other antibacterial drugs, PIVYA should be used only to treat or prevent infections that are
proven or strongly suspected to be caused by susceptible bacteria. When culture and
susceptibility information are available, they should be considered in selecting or modifying
antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns
may contribute to the empiric selection of therapy.
2 DOSAGE AND ADMINISTRATION
2.1 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 [see Clinical Pharmacology
(12.3)].

PIVYA (pivmecillinam) is a prodrug of mecillinam (the active antibacterial agent) [see Clinical
Pharmacology (12.3)].

2.2 Recommendations Regarding Missed Dose(s)

If a dose of PIVYA is missed, instruct patients to take the dose as soon as possible. Do not
double the dose to make up for the missed dose.
3 DOSAGE FORMS AND STRENGTHS

Each film-coated tablet contains 185 mg pivmecillinam (equivalent to 200 mg pivmecillinam

hydrochloride). The tablet is a white, circular film-coated tablet with a diameter of 9.5 mm,
debossed with “P” on one side and blank on the other.

4 CONTRAINDICATIONS

4.1 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) [see Warnings and Precautions (5.1)].

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 4.2 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) [see
Warnings and Precautions (5.3)].

4.3 Acute Porphyria

PIVYA is contraindicated in patients suffering from porphyria as pivmecillinam has been

associated with acute attacks of porphyria [see Warnings and Precautions (5.4)].

5 WARNINGS AND PRECAUTIONS

5.1 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 [see
Contraindications (4.1)]. If an allergic reaction occurs, discontinue PIVYA and institute
appropriate therapy.
5.2 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 [see Adverse Reactions (6.2)]. Monitor patients closely and discontinue PIVYA at
the first signs or symptoms of SCAR or other signs of hypersensitivity.

5.3 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 [see
Contraindications (4.2)].
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

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 therapies. Avoid concurrent treatment with valproic acid, valproate or other pivalate-generating
drugs due to increased risk of carnitine depletion [see Drug Interaction (7.1)].

5.4 Acute Porphyria

PIVYA is contraindicated in patients suffering from porphyria as pivmecillinam has been
associated with acute attacks of porphyria [see Contraindications (4.3)]. These episodes may be
life-threatening, and include symptoms and signs such as anxiety, confusion, limb or abdominal
pain, hyponatremia, seizures, and muscle weakness.

5.5 Clostridioides difficile-Associated Diarrhea

Clostridioides difficile-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.

5.6 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.

5.7 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.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described in greater detail in the
Warnings and Precautions section of labeling:
• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
• Carnitine Depletion [see Warnings and Precautions (5.3)]

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 • Acute Porphyria [see Warnings and Precautions (5.4)]
• Clostridioides difficile-Associated Diarrhea [see Warnings and Precautions (5.5)]

6.1 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

PIVYA* Placebo
N=282 N=288
Adverse Reactions (AR) n (%) 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.

6.2 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
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 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)

7 DRUG INTERACTIONS

7.1 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)
[see Warnings and Precautions (5.3)].
Pivmecillinam is a pivalate-generating prodrug [see Clinical Pharmacology (12.3)]. 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 [see Warnings and
Precautions (5.3)].
7.2 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.

7.3 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.

8 USE IN SPECIFIC POPULATIONS

8.1 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).
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 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 [see Warnings and
Precautions (5.7) and Drug Interactions (7.3)].

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 Cmax 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
8

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 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).

8.2 Lactation

Risk Summary
There are insufficient data to exclude the presence of mecillinam in human milk. Mecillinam is
present in animal milk (see Data). 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.

8.4 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 [see Warnings and Precautions (5.3)]. PIVYA is
contraindicated in patients with primary or secondary carnitine deficiency [see Contraindications
(4.2)].

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 [see Warnings and Precautions (5.7) and Drug
Interactions (7.3)].
9

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 8.5 Geriatric Use

Of the total number of PIVYA-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
PIVYA-treated patients evaluated for efficacy. A total of 19/579 (3%) of the PIVYA-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 PIVYA-treated patients evaluated for efficacy [see Adverse Reactions (6.1)
and Clinical Studies (14)].

No overall differences in safety or effectiveness of PIVYA have been observed between patients
65 years of age and older and younger adult patients.

Mecillinam pharmacokinetics data from geriatric patients are not available. PIVYA 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 [see Clinical
Pharmacology (12.3) and Use in Specific Populations (8.6)].

8.6 Renal Impairment

Reductions in systemic elimination as well as urinary excretion of mecillinam are anticipated
with decreases in renal function. The clinical significance of these changes on efficacy is
unknown. The available safety information does not suggest a need for dosage adjustment [see
Clinical Pharmacology (12.3)].

11 DESCRIPTION
PIVYA tablets contain pivmecillinam (as pivmecillinam hydrochloride), a penicillin class
antibacterial for oral administration. The chemical name of pivmecillinam hydrochloride is
methylene 2,2-dimethylpropanoate (2S,5R,6R)-6-[[(hexahydro-1H-azepin-1-
yl)methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate
hydrochloride. The molecular formula for pivmecillinam hydrochloride is C21H33N3O5S·HCl.
The molecular weight of pivmecillinam hydrochloride is 476.0 g/mol.
Figure 1: Chemical Structure of Pivmecillinam Hydrochloride

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 Each film-coated PIVYA tablet for oral administration contains 185 mg pivmecillinam
(equivalent to 200 mg pivmecillinam hydrochloride), and the following inactive ingredients:
cellulose microcrystalline, hydroxypropyl cellulose, hypromellose, magnesium stearate, paraffin,
and simethicone.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

PIVYA is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Like other beta-lactam antibacterial drugs, the bacteriological effect of PIVYA in the treatment
of uUTI is dependent on time above minimum inhibitory concentration (MIC), which has been
shown to best correlate with efficacy in animal models of infection against E. coli.
12.3 Pharmacokinetics
Pivmecillinam is a pro-drug of mecillinam (the active antibacterial moiety). The pharmacokinetic
information for mecillinam from published studies is summarized in Table 2.

Table 2: Summary of Pharmacokinetic Parameters and Properties of Mecillinam in

Healthy Females Receiving a Single Dose of 185 mg Pivmecillinam

Parameter Value (Mean ± SD)

General Information

Exposure (Day 1)

Cmax (mcg/mL) 1.7 ± 1.1

AUC0-8 hours (mcg∙min/mL) 214 ± 44

Accumulation No clinically significant accumulation

Absorption
Oral bioavailability of
25-35%
mecillinam*
Tmax (min) 90 ± 33

Effect of food No clinically significant effect on Mecillinam PK

Distribution

% plasma protein binding <25%

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 Apparent volume of distribution
51
(L)
Elimination

Oral clearance (mL/min) 580 ± 100

Terminal half-life (min) 61 ± 32

Metabolism
• Pivmecillinam is converted to mecillinam (active
antibacterial moiety) and pivalic acid by non-specific
Metabolic pathways esterases.
• Mecillinam undergoes minimal metabolism.

Excretion

Major route of elimination Urinary excretion , primarily as mecillinam (80% of dose)

Cmax=maximum plasma concentration; AUC0-8 hours=area under the plasma concentration-time curve from time zero to 8
hours;Tmax=time to Cmax
*Bioavailability estimate based on comparison of dose normalized mecillinam exposure after 185 mg oral pivmecillinam
administration and 200 mg IV mecillinam.
†Excretion estimate based on PK data following intravenous administration of mecillinam.

Specific Populations
The effect of age, sex, race and body weight on pivmecillinam or mecillinam pharmacokinetics
is unknown.
Patients with Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of mecillinam have not been
evaluated. Hepatic impairment is not expected to alter the elimination of mecillinam as hepatic
metabolism/excretion represents a minor pathway of elimination for mecillinam. Dosage
adjustments are not necessary in patients with impaired hepatic function.
Patients with Renal Impairment
In published pharmacokinetic studies, mecillinam systemic elimination and urinary excretion
decreases with degree of renal function.
Drug Interaction Studies
Clinical Studies
OAT1/3 inhibitors: Mean mecillinam Cmax increased by approximately 80% and AUC by
approximately 40% following concomitant use of oral probenecid (OAT1/3 inhibitor) with
pivmecillinam in two published studies.
MATE1 or MATE2K inhibitors: The effect of concomitant use on pivmecillinam or mecillinam
pharmacokinetics is unknown.
In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically

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 Cytochrome P450 (CYP) enzymes: Mecillinam does not inhibit nor induce CYP 1A1, 1A2, 2A6,
2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5.
Transporter systems: 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.

12.4 Microbiology
Mechanism of Action
Pivmecillinam is the pro-drug containing the pivaloyloxymethylester of the amidinopenicillanic
acid, mecillinam. Orally administered, pivmecillinam is well absorbed and subsequently rapidly
hydrolyzed to mecillinam, the active antibacterial agent, by non-specific esterases present in
blood, gastrointestinal mucosa and other tissues. Mecillinam is a beta-lactam antibacterial drug
with a targeted spectrum of activity. It is mainly active against gram-negative bacteria and works
by interfering with the biosynthesis of the bacterial cell wall. Unlike the majority of other beta-
lactam agents, which preferentially bind gram-negative PBP-1A, -1B or -3, mecillinam exerts
high specificity against penicillin-binding protein-2 (PBP-2) in the gram-negative cell wall.
Resistance
Mecillinam demonstrated in vitro activity against Enterobacterales in the presence of some beta-
lactamases and extended-spectrum beta-lactamases (ESBL) of the following groups: CTX-M,
SHV, TEM and AmpC.
The inhibitory action of mecillinam on PBP-2 results in low cross-resistance with certain beta-
lactams. The frequency of resistance to mecillinam in E. coli range from 8×10-8 to 2×10-5 when
exposed to 32-256 times MIC.
Interaction With Other Antimicrobials
PIVYA has demonstrated synergy with other beta-lactams. In vitro antagonism has been shown
with nitrofurantoin.
Antimicrobial Activity
PIVYA has been shown to be active against most isolates of the following microorganisms both
in vitro and in clinical infections [see Indications and Usage (1)].
Aerobic Bacteria
Gram-negative Bacteria
o Escherichia coli
o Proteus mirabilis
Gram-positive Bacteria

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 o Staphylococcus saprophyticus

The following in vitro data are available, but their clinical significance is unknown. At least 90
percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC)
less than or equal to the susceptible breakpoint for PIVYA against isolates of similar genus or
organism group. However, the efficacy of PIVYA in treating clinical infections caused by these
bacteria has not been established in adequate and well-controlled clinical trials.
Aerobic Bacteria
Gram-negative Bacteria
o Citrobacter freundii
o Enterobacter cloacae
o Klebsiella pneumoniae
o Klebsiella aerogenes
o Klebsiella oxytoca
Susceptibility Testing
For specific information regarding susceptibility test interpretive criteria, and associated test
methods and quality control standards recognized by FDA for this drug, please see
https://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

Carcinogenicity studies have not been conducted with pivmecillinam or mecillinam.

Mutagenesis

Pivmecillinam was mutagenic in the Ames bacterial reverse mutation assay. Pivmecillinam
induced chromosome breaks in cultured human lymphocytes, but did not induce damage to
mouse bone marrow cell chromosomes in vivo. The positive findings observed in the in vitro
studies are considered to be due to the release of formaldehyde from the pivoxil ester moiety of
pivmecillinam because they were not observed when mecillinam was tested in the same assays.
The positive findings are not considered relevant to the clinical use of PIVYA because the small
amount of formaldehyde released is eliminated quickly in vivo, but not in vitro.

Impairment of Fertility

Mecillinam had no adverse effect on fertility in male or female rats at subcutaneous doses up to
450 mg/kg/day (approximately 7.9-fold higher than the maximum recommended daily human
dose based on body surface area). Pivmecillinam had no adverse effect on fertility in male or
female rats at oral doses up to 582 mg/kg/day (approximately 10.2-fold higher than the
maximum recommended daily human dose based on body surface area).

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 14 CLINICAL STUDIES

Three controlled clinical trials comparing different PIVYA dosing regimens to placebo (Trial 1),
to another oral antibacterial drug (Trial 2), or to ibuprofen (Trial 4) evaluated the efficacy of
pivmecillinam for the treatment of uUTI. Efficacy was assessed in the Microbiological Intent-to-
Treat (micro-ITT) population which included all randomized subjects with a positive baseline
urine culture defined as ≥105 colony-forming-units (CFU)/mL of a uropathogen where CFU
count was available and no more than 2 species of microorganisms, regardless of colony count,
and no baseline pathogen was non-susceptible to the active comparator. The composite response
rates (composite endpoint of clinical cure and microbiological response), as well as clinical cure
and microbiological response rates of the recommended 185 mg three times daily dosing
regimen are summarized in Table 3, Table 4 and Table 5.

Trial 1 was a multi-center, randomized, double-blinded study in Sweden evaluating the efficacy
of 3 dosage regimens of PIVYA tablets (185 mg three times daily for 7 days, 185 mg two times
daily for 7 days (not an approved dosing regimen for PIVYA), and 370 mg two times daily for 3
days (not an approved dosing regimen for PIVYA)) compared to placebo in women 18 years of
age or older with symptoms of uUTI. The trial enrolled patients with mean age of 45 years with
E. coli as the most common baseline pathogen. PIVYA demonstrated efficacy for the composite
response of clinical cure and microbiological response at Day 8-10. Clinical cure was defined as
no persisting symptoms during and post-therapy. Microbiological response for the initial
pathogen at follow-up visits was defined as reduction in the number of bacteria to <103 CFU/mL.
Composite response was achieved in 85/137 (62%) of patients in the PIVYA group and 14/134
(10%) in the placebo group at TOC in the micro-ITT population.

Trial 2 was a multi-center, randomized, double-blinded study in the U.S. evaluating the efficacy
and safety of PIVYA tablets 185 mg three times a day for 3 days compared to cephalexin 250 mg
four times daily for 7 days in females 18 years of age or older with uUTI. The trial enrolled
patients with a mean age of 31 years, who were 85% White and 12% Black or African American
with E. coli as the most common baseline pathogen. Clinical cure was defined as no persisting
symptoms during and post-therapy. Microbiological response was defined as negative urine
culture (<103 CFU/mL) for the initial pathogen at Day 10. Composite response was achieved in
91/127 (72%) of patients in the PIVYA group and 100/132 (76%) in the cephalexin group at the
TOC in the micro-ITT population.
Trial 4 (NCT01849926) was a multi-center, randomized, double-blinded, non-inferiority study in
Denmark, Norway, and Sweden to evaluate the efficacy and safety of PIVYA tablets 185 mg
three times daily for 3 days compared to ibuprofen 600 mg three times daily for 3 days in women
18 to 60 years of age with clinical symptoms of uUTI. The trial enrolled patients with mean age
of 29 years with E. coli as the most common baseline pathogen. PIVYA demonstrated efficacy
for the composite response (clinical cure and microbiological response) at TOC (Day 14).
Clinical cure was defined as the patient reporting no symptoms at Day 7 and reporting no
symptoms at Day 14. Microbiological response was defined as negative urine culture (<103
CFU/mL) for the initial pathogen at Day 14. Composite response was achieved in 69/105 (66%)

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 in the PIVYA group and 26/119 (22%) in the ibuprofen group at TOC in the micro-ITT
population.
Table 3: Composite Response Rates (Clinical Cure and Microbiological Response) at
TOC in the uUTI trials (Micro-ITT Population)
Composite Response Rates
(Clinical Cure and Microbiological
Response)
Trial 1 PIVYA Placebo Difference
N=137, N=134, (95% CI)
n (%)
n (%)
85 (62) 14 (10) 52 (41, 62)

Trial 2 PIVYA Cephalexin

N=127, N=132,
n (%) n (%)
91 (72) 100 (76) -4 (-16, +7)

Trial 4 PIVYA Ibuprofen

N=105, N=119,
n (%) n (%)
69 (66) 26 (22) 44 (31, 57)

Table 4: Clinical Cure Rates (Micro-ITT Population) at TOC in the uUTI trials

Clinical Cure Rates

Trial 1 PIVYA Placebo Treatment

N=137, N=134, Difference (95% CI)
n (%) n (%)
87 (64) 31 (23) 40 (29, 52)

Trial 2 PIVYA Cephalexin

N=127, N=132,
n (%) n (%)
105 (83) 112 (85) -2 (-12, +8)

Trial 4 PIVYA Ibuprofen

N=105, N=119,
n (%) n (%)
81 (77) 45 (38) 39 (27, 52)

Table 5: Microbiological Response Rates (Micro-ITT Population) at TOC in the uUTI

trials

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 Microbiological Response Rates

Trial 1 PIVYA Placebo Treatment

N=137, N=134, difference
n (%) n (%) (95% CI)

119 (87) 35 (26) 61 (51,71)

Trial 2 PIVYA Cephalexin

N=127, N=132,
n (%) n (%)
97 (76) 106 (80) -4 (-15, +7)

Trial 4 PIVYA Ibuprofen

N=105, N=119,
n (%) n (%)
78 (74) 64 (54) 21 (7, 34)

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

PIVYA tablets are supplied as 185 mg pivmecillinam tablets, film-coated in child-resistant

aluminum-aluminum push-through blisters.
Available pack sizes:

9 tablets (1 blister sheet with 9 tablets) NDC 82456-200-09.

50 tablets (5 blister sheets with 10 tablets per blister sheet) NDC 82456-200-50.

The tablet is white, circular, film-coated, debossed with “P” on one side and blank on the other .
Size: Approx. 9.5 mm in diameter.

16.2 Storage and Handling

Store PIVYA tablets at 20oC to 25oC (68oF to 77oF); excursions permitted between 15°C to 30°C
(59°F to 86°F) [See USP Controlled Room Temperature]. Store and dispense tablets in the unit-
dose blisters.

17 PATIENT COUNSELING INFORMATION

Hypersensitivity Reactions
Advise patients that allergic reactions, including serious allergic reactions, could occur with
PIVYA and that serious reactions require immediate treatment. Ask patients about previous
hypersensitivity reactions to penicillins, cephalosporins, carbapenems, and other beta-lactam
antibacterials. Advise the patient to call their healthcare provider immediately if they develop a
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 new rash, urticaria, drug eruptions, swelling of the face, difficulty in breathing or other
symptoms of allergic reactions [see Warnings and Precautions (5.1)].

Severe Cutaneous Adverse Reactions

Advise patients about the signs and symptoms of severe cutaneous adverse reactions. Advise the
patient to discontinue PIVYA if they develop any type of skin rash, mucosal lesions or any other
sign of hypersensitivity and to seek immediate medical attention [see Warnings and Precautions
(5.2)].
Drug Interactions
Advise patients to avoid use of valproic acid, valproate or other pivalate-generating drugs due to
increased risk of carnitine depletion [see Warnings and Precautions (5.3)].

Diarrhea
Counsel patients that diarrhea is a common problem caused by antibacterial drugs, including
PIVYA, and it usually ends when the drug is discontinued. Sometimes after starting treatment
with antibacterial drugs, patients can develop watery and bloody stools (with or without stomach
cramps and fever) even as late as two or more months after taking the last dose of the drug.
Advise patients to seek medical attention as soon as possible if this occurs [see Warnings and
Precautions (5.5)].
Antibacterial Resistance
Patients should be counseled that antibacterial drugs including PIVYA should only be used to
treat bacterial infections. They do not treat viral infections (e.g., the common cold). When
PIVYA is prescribed to treat a bacterial infection, patients should be told that although it is
common to feel better early in the course of therapy, the medication should be taken exactly as
directed. Skipping doses or not completing the full course of therapy may (1) decrease the
effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will
develop resistance and will not be treatable by PIVYA or other antibacterial drugs in the future.
Interference with Newborn Screening Test
Advise patients that 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 and
prompt follow-up of a positive result is recommended [see Warnings and Precautions (5.7)].
Missed Doses
If a dose of PIVYA is missed, instruct patients to take the dose as soon as possible. Instruct
patients not to double the dose to make up for the missed dose.

Manufactured for: UTILITY therapeutics Ltd, UK

Manufactured by: Recipharm Strängnäs AB, Mariefredsvägen 35, S-645 41 Strängnäs, Sweden
Distributed by : UTILITY therapeutics Ltd, 1 Shetland Road, Florham Park, NJ. 07932

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