Pivmecillinam

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.