El Saad Pharma

Product Name	:	ALSAPEN
Chemical Name	:	Penicillin G (Sodium)
Therapeutic Category	:	Antimicrobial
Pharmacologic Category	:	Antibiotic, Penicillin
Pharmaceutical Form	:	Vial
Composition	:	Penicillin G (Sodium) 1000000 IU / 3000000 IU

Dosing		Dosing: Adult Actinomyces species: I.V.: 10-20 million units/day divided every 4-6 hours for 4-6 weeks Clostridium perfringens: I.V.: 24 million units/day divided every 4-6 hours with clindamycin Corynebacterium diphtheriae: I.V.: 2-3 million units/day in divided doses every 4-6 hours for 10-12 days Erysipelas: I.V.: 1-2 million units every 4-6 hours Erysipelothrix: I.V.: 2-4 million units every 4 hours Fascial space infections: I.V.: 2-4 million units every 4-6 hours with metronidazole Leptospirosis: I.V.: 1.5 million units every 6 hours for 7 days Listeria: I.V.: 15-20 million units/day in divided doses every 4-6 hours for 2 weeks (meningitis) or 4 weeks (endocarditis) Lyme disease (meningitis): I.V.: 20 million units/day in divided doses Neurosyphilis: I.V.: 18-24 million units/day in divided doses every 4 hours (or by continuous infusion) for 10-14 days (CDC, 2006; CDC, 2009; CDC, 2010) Streptococcus: Brain abscess: I.V.: 18-24 million units/day in divided doses every 4 hours with metronidazole Endocarditis or osteomyelitis: I.V.: 3-4 million units every 4 hours for at least 4 weeks Pregnancy (prophylaxis GBS): I.V.: 5 million units x 1 dose, then 2.5 million units every 4 hours until delivery (ACOG, 2002; CDC, 2002) Skin and soft tissue: I.V.: 3-4 million units every 4 hours for 10 days Toxic shock: I.V.: 24 million units/day in divided doses with clindamycin Streptococcal pneumonia: I.V.: 2-3 million units every 4 hours Whipple's disease: I.V.: 2 million units every 4 hours for 2 weeks, followed by oral trimethoprim/sulfamethoxazole or doxycycline for 1 year Relapse or CNS involvement: 4 million units every 4 hours for 4 weeks Dosing: Pediatric Susceptible infections: I.M., I.V.: Infants ≥1 month and Children: 100,000-400,000 units/kg/day in divided doses every 4-6 hours (maximum dose: 24 million units/day) Meningitis (gonococcal): I.V.: 250,000 units/kg/day in 4 divided doses Moderate infections: I.M., I.V.: 100,000-250,000 units/kg/day in 4 divided doses Neurosyphilis: I.V.: 200,000-300,000 units/kg/day divided every 4-6 hours for 10-14 days (maximum dose: 24 million units/day) Severe infections: I.M., I.V.: 250,000-400,000 units/kg/day in divided doses every 4-6 hours (maximum dose: 24 million units/day) Syphilis (congenital): I.V.: Infants: 50,000 units/kg every 12 hours for first 7 days of life, then every 8 hours for a total of 10 days (CDC, 2010) Children: 50,000 units/kg every 4-6 hours for 10 days (CDC, 2010) Dosing: Geriatric Refer to adult dosing. Dosing: Renal Impairment Uremic patients with Clcr >10 mL/minute/1.73 m2: Administer full loading dose followed by 1/2 of the loading dose given every 4-5 hours Clcr <10 mL/minute/1.73 m2: Administer full loading dose followed by 1/2 of the loading dose given every 8-10 hours Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): Administer normal loading dose followed by either 25% to 50% of normal dose every 4-6 hours or 50% to 100% of normal dose every 8-12 hours. For mild-to-moderate infections, administer 0.5-1 million units every 4-6 hours or 1-2 million units every 8-12 hours. For neurosyphilis, endocarditis, or serious infections, administer up to 2 million units every 4-6 hours; administer after dialysis on dialysis days or supplement with 500,000 units after dialysis (Heintz, 2009). Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions. Continuous renal replacement therapy (CRRT) (Heintz, 2009; Trotman, 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1-2 L/hour and minimal residual renal function) and should not supersede clinical judgment: CVVH: Loading dose of 4 million units, followed by 2 million units every 4-6 hours CVVHD: Loading dose of 4 million units, followed by 2-3 million units every 4-6 hours CVVHDF: Loading dose of 4 million units, followed by 2-4 million units every 4-6 hours

Use		Treatment of infections (including sepsis, pneumonia, pericarditis, endocarditis, meningitis, anthrax) caused by susceptible organisms; active against some gram-positive organisms, generally not Staphylococcus aureus; some gram-negative organisms such as Neisseria gonorrhoeae, and some anaerobes and spirochetes

Adverse Reactions		Frequency not defined. Central nervous system: Coma (high doses), hyper-reflexia (high doses), seizures (high doses) Dermatologic: Contact dermatitis, rash Endocrine & metabolic: Electrolyte imbalance (high doses) Gastrointestinal: Pseudomembranous colitis Hematologic: Neutropenia, positive Coombs' hemolytic anemia (rare, high doses) Local: Injection site reaction, phlebitis, thrombophlebitis Neuromuscular & skeletal: Myoclonus (high doses) Renal: Acute interstitial nephritis (high doses), renal tubular damage (high doses) Miscellaneous: Anaphylaxis, hypersensitivity reactions (immediate and delayed), Jarisch-Herxheimer reaction, serum sickness

Contraindications		Hypersensitivity to penicillin or any component of the formulation

Warnings / Precautions Drug		Concerns related to adverse Adverse Reactions Significant • Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity, history of sensitivity to multiple allergens, or previous IgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria). Use with caution in asthmatic patients. • Neurovascular damage: Avoid intra-arterial administration or injection into or near major peripheral nerves or blood vessels since such injections may cause severe and/or permanent neurovascular damage. • Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment. Disease-related concerns: • Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended. In the presence of concomitant hepatic impairment, further dosage adjustment may be needed. • Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures. Special populations: • Pediatrics: Neonates may have decreased renal clearance of penicillin and require frequent dosage adjustments depending on age. Other warnings/Warnings/Precautions • Electrolyte imbalance: Product contains sodium and potassium; high doses of I.V. therapy may alter serum levels. • Prolonged use: Extended duration of therapy or use associated with high serum concentrations (eg, in renal insufficiency) may be associated with an increased risk for some adverse reactions (neutropenia, hemolytic anemia, serum sickness).

Interactions		BCG: Antibiotics may diminish the therapeutic effect of BCG. Risk X: Avoid combination Fusidic Acid: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification Methotrexate: Penicillins may decrease the excretion of Methotrexate. Risk C: Monitor therapy Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Risk C: Monitor therapy Probenecid: May increase the serum concentration of Penicillins. Risk C: Monitor therapy Tetracycline Derivatives: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 24 hours after cessation of antibacterial agents. Risk D: Consider therapy modification

Pregnancy		B Pregnancy Implications Adverse events have not been observed in animal studies; therefore, penicillin G is classified as pregnancy category B. Penicillin crosses the placenta and distributes into amniotic fluid. There is no evidence of adverse fetal effects after penicillin use during pregnancy in humans. Penicillin G is the drug of choice for treatment of syphilis during pregnancy and penicillin G (parenteral/aqueous) is the drug of choice for the prevention of early-onset Group B Streptococcal (GBS) disease in newborns.

Lactation		Enters breast milk/compatible Breast-Feeding Considerations Very small amounts of penicillin G transfer into breast milk. Peak milk concentrations occur at approximately 1 hour after an IM dose and are higher if multiple doses are given. The manufacturer recommends that caution be exercised when administering penicillin to nursing women. Nondose-related effects could include modification of bowel flora and allergic sensitization.

Mechanism of Action		Interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity against susceptible bacteria

Pharmacodynamics / Kinetics		Distribution: Poor penetration across blood-brain barrier, despite inflamed meninges Relative diffusion from blood into CSF: Poor unless meninges inflamed (exceeds usual MICs) CSF:blood level ratio: Normal meninges: <1%; Inflamed meninges: 2% to 6% Protein binding: 65% Metabolism: Hepatic (30%) to penicilloic acid Half-life elimination: Neonates: <6 days old: 3.2-3.4 hours; 7-13 days old: 1.2-2.2 hours; >14 days old: 0.9-1.9 hours Children and Adults: Normal renal function: 30-50 minutes End-stage renal disease: 3.3-5.1 hours Time to peak, serum: I.M.: ~30 minutes; I.V.: ~1 hour Excretion: Urine (58% to 85% as unchanged drug)