PIVYA

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 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. image description

PIVYA is a penicillin class antibacterial 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, Proteus mirabilis and Staphylococcus saprophyticus . ( 1.1 ) 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 bacteria. ( 1.2 ) 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.

The recommended dosage of PIVYA is one 185 mg tablet orally 3 times a day for 3 to 7 days as clinically indicated. ( 2.1 ) Administer PIVYA with or without food. ( 2.1 ) 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 notdouble the dose to make up for the missed dose.

Serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to PIVYA or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins). ( 4.1 ) 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). ( 4.2 ) Acute porphyria. ( 4.3 ) 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 ) ]. 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 )] .

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 )] Acute Porphyria [see Warnings and Precautions ( 5.4 )] Clostridioides difficile -Associated Diarrhea [see Warnings and Precautions ( 5.5 )] The most common adverse reactions observed in ≥2% of the patients receiving PIVYA in clinical trials are nausea and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Therapeutics at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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. 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 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)

7.1 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.

16.2 Storage and Handling Store PIVYA tablets at 20 o C to 25 o C (68 o F to 77 o F); 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.