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warnings and cautions
5. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Serious hypersensitivity reactions including anaphylaxis have been reported in patients treated with PIVYA. If hypersensitivity reactions occur, discontinue treatment with PIVYA and institute appropriate therapy. ( 5.1 ) Severe Cutaneous Adverse Reactions (SCAR) : Acute Generalized Exanthematous Pustulosis (AGEP), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Steven-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. ( 5.2 ) Carnitine Depletion : Clinically significant hypocarnitinemia has been observed in patients at risk for reductions in serum carnitine. In patients with significant renal impairment or decreased muscle mass and those patients requiring long term antimicrobial treatment, consider alternative antibacterial therapies. PIVYA is not recommended when prolonged antibacterial treatment is necessary. Avoid concurrent treatment with valproic acid, valproate or other pivalate-generating drugs due to increased risk of carnitine depletion. ( 5.3 ) Clostridioides difficile -Associated Diarrhea (CDAD) : This has been reported for nearly all systemic antibacterial agents, including PIVYA. Evaluate if diarrhea occurs. ( 5.5 ) 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. ( 5.7 ) 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 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-a ssociated 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 )] 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)