TIENAM Merck Sharp & Dhome 1. NAME OF THE MEDICINAL PRODUCT TIENAM® I.V. TIENAM® I.M. TIENAM® I.M. with Lidocaine HCl 1%. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION ‘Tiënam’ I.V. is a sterile powder for injection fluid in a 115-ml vial containing imipenem monohydrate equivalent to 500 mg imipenem anhydrate and cilastatin sodium equivalent to 500 mg cilastatin. There is also a 60 ml vial containing half these amounts. ‘Tiënam’ I.M. is supplied as a sterile powder for injection fluid in vials containing either imipenem monohydrate and cilastatin sodium equivalent to 500 mg or 750 mg imipenem anhydrate and cilastatin when reconstituted. The I.M. formulation is not for I.V. use. Combination package: ‘Tiënam’ I.M. with Lidocaine HCl 1%, bottle containing the above combined with 1 (for the 500 mg vial) or 2 (for the 750 mg vial) ampoules (2  ml) containing lidocaine hydrochloride monohydrate, equivalent to 20 mg lidocaine hydrochlori¬de (10 mg/ml).

‘Tiënam’ can be used for the treatment of mixed infections caused by susceptible strains of aerobic and anaerobic bacteria. ‘Tiënam’ is not indicated for the treatment of meningitis. The intravenous route and formulation of ‘Tiënam’ is to be used for therapy for bacterial sepsis or endocarditis or other severe or life threatening infections including lower respiratory tract infections caused by Pseudomonas spp., and in instances of major physiological impairments such as shock. Systemic infections with relatively unsusceptible bacteria, such as Pseudomonas and Proteus spp., should not be considered for treatment with ‘Tiënam’ I.M. The intramuscular formulation of ‘Tiënam’ may be used as an alternative to the intravenous formulation in the treatment of those infections for which intramuscular therapy is appropriate. Lidocaine HCL Lidocaine HCl is used as a local anesthetic, to be used only for reconstitution of ‘Tiënam’ I.M.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION 3. PHARMACEUTICAL FORM ‘Tiënam’ is available in two different formulations, Sterile powders for intravenous and intramuscular one for intravenous infusion only and one for intrainjection. In combination package also injection fluid. muscular injection only. The intramuscular formulation must not be used intravenously. 4. CLINICAL PARTICULARS Dosage and administration recommendations for the 4.1 THERAPEUTIC INDICATIONS Infections due to organisms susceptible to ‘Tiënam’. intravenous infusion are presented first. Dosage and administration recommendations for the - intra-abdominal infections intramuscular injection follow the intravenous infu- lower respiratory tract infections sion section. - septicemia* The dosage recommendations for ‘Tiënam’ repre-  genitourinary tract infections sent the quantity of imipenem to be administered. - bone and joint infections An equivalent amount of cilastatin is also present in - skin and soft-tissue infections the solution. - endocarditis* * Not indicated for therapy with the intramuscular The total daily dosage and route of administration of ‘Tiënam’ should be based on the type or severity of formulation.

TIENAM - p.2/10 infection and given in equally divided doses based function have been treated with ‘Tienam’ at doses on consideration of degree of susceptibility of the up to 90 mg/kg/day in divided doses, not exceeding 4 g/day. pathogen(s), renal function and body weight. Intravenous infusion Adult dosage schedule for patients with normal renal function Doses cited in table 1 are based on a patient with normal renal function (creatinine clearance of >70 ml/min/1.73 m2) and a body weight of ≥70 kg. A reduction in dose must be made for a patient with a creatinine clearance of ≤70 ml/min/1.73 m2 (see table 2) and/or a body weight 500 mg should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed. Table 1. I.V. dosage schedule for adults with normal renal function and body weight ≥70kg* Severity of Dose of imipe- Dose interval Total daily infection nem (mg) (hrs) dosage (g) Mild 250 6 1 Moderate 500 8 1.5 1000 12 2 Severe - fully 500 6 2 susceptible Severe and/or life threaten1000 6-8 3-4 ing **

* A  further proportionate reduction in dose administered must be made for patients with a body weight 2 to 4 g per day, the overall safety profile is similar to that seen at lower dosages. The most common adverse reactions have been local reactions. Local reactions Erythema, local pain and induration, thrombophlebitis. Allergic reactions/skin Rash, pruritus, urticaria, erythema multiforme, Stevens-Johnson syndrome, angioedema, toxic epidermal necrolysis (rarely), exfoliative dermatitis (rarely), candidiasis, fever, anaphylactic reactions. Gastrointestinal reactions Nausea, vomiting, diarrhea, staining of teeth. In common with virtually all other broad spectrum antibiotics, pseudomembranous colitis has been reported. Blood Eosinophilia, leukopenia, neutropenia, including agranulocytosis, thrombocytopenia, thrombocytosis, decreased hemoglobin, pancytopenia, bone marrow depression and prolonged prothrombin time have been reported. A positive direct Coombs test may develop in some individuals. Liver function Increases in serum transaminases, bilirubin and/or alkaline phosphatase, hepatitis (rarely).

Renal function Oliguria/anuria, polyuria, acute renal failure (rarely). In such cases predisposing factors usually were present. Elevations in serum creatinine and blood urea nitrogen have been reported. Urine discoloration. This is 4.7 EFFECTS ON ABILITY TO DRIVE AND USE harmless and should not be confused with hematuria. MACHINES There are no specific data. Some of the undesirable Nervous system/psychiatric effects such as psychic disturbances, confusion, sei- As with other beta-lactam antibiotics, CNS adverse

TIENAM - p.6/10 experiences such as myoclonic activity, psychic disturbances, including hallucinations, confusional states, or seizures have been reported with the I.V. formulation. Paresthesia.

Imipenem and cilastatin sodium components may cause effects as described under Adverse events’. See also the passage concerning ‘The central nervous system’ in the Special warnings section. In view of the Lidocaine HCl quantity in the preparaSpecial senses tion, only a mild intoxication is expected in case of Hearing loss, taste perversion. an overdosage. Symptoms that may arise include: Granulocytopenic patients tremors, nausea, vomiting, hypotension and bradyDrug-related nausea and/or vomiting appear to cardia. Bronchospasms may occur. Imipenem/cilasoccur more frequently in granulocytopenic patients tatin sodium can be dialyzed. It is unknown whether than in non-granulocytopenic patients treated with this procedure will remedy an overdosage. ‘Tiënam’ I.V. Treatment is symptomatic and supportive in all cases. ADDITIONAL SIDE-EFFECTS For the following side-effects, a causal relationship has not been established: Gastrointestinal: hemorrhagic colitis, gastroenteritis, abdominal pain, glossitis, tongue papillar hypertrophy, heartburn, pharyngeal pain, increased salivation. Central nervous system: dizziness, somnolence, encephalopathy, vertigo, headache. Special senses: tinnitus. Respiratory: chest discomfort, dyspnea, bronchospasm, hyperventilation, thoracic spine pain. Cardiovascular: hypotension, palpitations, tachycardia. Skin: flushing, cyanosis, hyperhidrosis, skin texture changes, pruritus vulvae. Body as a whole: polyarthralgia, asthenia/weakness. Blood: hemolytic anemia.

5. PHARMACOLOGICAL PROPERTIES 5.1 PHARMACODYNAMIC PROPERTIES ‘Tiënam’ (imipenem/cilastatin sodium) is a broad spectrum beta-lactam antibiotic supplied in two different formulations ‘Tiënam’ I.V. for intravenous infusion only, ‘Tiënam’ I.M. for intramuscular injection only. ‘Tiënam’ consists of two components: (1) imipenem, the first of a new class of beta-lactam antibiotics, the thienamycins; and (2) cilastatin sodium, a specific enzyme inhibitor that blocks the metabolism of imipenem in the kidney, and substantially increases the concentration of intact imipenem in the urinary tract. Imipenem and cilastatin sodium are present in ‘Tiënam’ in a 1:1 ratio by weight. Imipenem, also referred to as N-formimidoylthienamycin, is a semi-synthetic derivative of thienamycin, the parent compound produced by the filamentous bacterium Streptomyces cattleya. Cilastatin sodium is a competitive, reversible and specific inhibitor of dehydropeptidase-I, the renal enzyme which metabolizes and inactivates imipenem. It is devoid of intrinsic antibacterial activity and does not affect the antibacterial activity of imipenem.

Lidocaine HCl Severe adverse reactions usually result from excessive dosage or technical errors (accidental intravascular injection). See the overdosage section. In view of the total quantity of Lidocaine HCl in the preparation, the risk of Lidocaine HCl-related adverse Microbiology events is limited. Hypersensitivity to Lidocaine HCl ‘Tiënam’ is a potent inhibitor of bacterial cell wall occurs only rarely. synthesis and is bactericidal against a broad spectrum of pathogens, gram-positive and gram-nega4.9 OVERDOSE No specific data are available on overdosage with tive, aerobic and anaerobic. ‘Tiënam’. ‘Tiënam’ shares with the newer cephalosporins

TIENAM - p.7/10 and penicillins a broad spectrum of activity against gram-negative species, but its high potency against gram-positive species was previously associated only with earlier narrow-spectrum beta-lactam antibiotics. The spectrum of activity of ‘Tiënam’ includes Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis and Bacteroides fragilis, a diverse group of problem pathogens. Imipenem is resistant to degradation by bacterial beta-lactamases and is often active against microorganisms resistant to other beta-lactam antibiotics. Organisms against which ‘Tiënam’ is usually active in vitro include: AEROBIC BACTERIA gram-negative: MIC90 0,01MIC90 0,1-1 µg/ml 0,1 µg/ml Campylobacter spp. Escherichia coli Campylobacter fetus spp. jejuni

MIC90 1-10 µg/ml Proteus mirabilis Proteus vulgaris

Serratiproteamaculans Proteus spp. (formerly Serratia liq- Serratia marcesuefaciens) cens Serratia spp Enterobacter aeroMorganella morgenes ganii Enterobacter agglomerans Klebsiella oxytoca Providencia rettgeri Klebsiella pneumoniae Providencia stuartii Klebsiella spp. Providencia spp. Citrobacter freundii Citrobacter diversus Citrobacter spp. Enterobacter cloacae Salmonella typhi Enterobacter spp. Salmonella spp.

Pseudomonas aeruginosa Shigella spp. Pseudomonas fluorescens Acinetobacter spp. Pseudomonas spp.* Neisseria gonorrhoeae Haemophilus influenzae Neisseria meningitidis Heamophilus parainfluenzae

Yersinia spp.(formerly Gardnerella vagiPasteurella) nalis Yersinia enteroco-litica Yersinia pseudotubercolosis

* Xanthomonas maltophilia (formerly Pseudomonas maltophilia and some strains of Pseudomonas cepacia are generally not susceptible to ‘Tiënam’.

gram positive Streptococcus pyo- Streptococcus genes group D (including entero-cocci) Streptococcus aga- non-entero-cocci lactiae Staphylococcus epidermidis Listeria monocytogenes Streptococcus group C Streptococcus pneumoniae Streptococcus viridans

Staphylococcus aureus Enterococcus feacalis

Some meticillin-resistant staphylococci and some group D streptococci are not susceptible to ‘Tiënam’. ANAEROBIC BACTERIA gram-negative: Bacteroides fragilis Fusobacterium spp. Bacteroides spp. Veillonella spp. gram-positive Peptococcus spp. Propionibacterium spp. Propionibacterium acnes

Actinomyces spp. Eubacterium spp. Clostridium perfringens Clostridium spp. Peptostreptococcus spp.

In vitro tests show imipenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa. None of the organisms in the column MIC90 (1-10) has MIC value higher than 8 µg/ml. Lidocaine HCl Lidocaine HCl is a short-acting local anesthetic of the amide type with a rapid onset of action and a high dregree of anesthetic efficacy. Its mechanism

TIENAM - p.8/10 of action involves a reduced permeability to sodium ions of the nerve cell membrane. As a result, repolarization rate is reduced and the excitation threshold is increased leading to a reversible local insensibility. 5.2 PHARMACOKINETIC PROPERTIES Imipenem: In normal volunteers, intravenous infusion of ‘Tiënam’ over 20 minutes resulted in peak plasma levels of imipenem ranging from 12 to 20 µg/ml for the 250-mg dose, from 21 to 58 µg/ml for the 500-mg dose, and from 41 to 83 µg/ml for the 1000-mg dose. The mean peak plasma levels of imipenem following the 250, 500 and 1000-mg doses were 17, 39 and 66 µg/ml, respectively. At these doses, plasma levels of imipenem antimicrobial activity decline to below 1 µg/ml or less in four to six hours. The plasma half-life of imipenem was one hour. Approximately 70% of the administered antibiotic was recovered intact in the urine within ten hours, and no further urinary excretion of the drug was detectable. Urine concentrations of imipenem exceeded 10 µg/ml for up to eight hours after a 500mg dose of ‘Tiënam’. The remainder of the administered dose was recovered in the urine as antibacterially inactive metabolites, and fecal elimination of imipenem is essentially nil. No accumulation of imipenem in plasma or urine has been observed with regimens of ‘Tiënam’, administered as frequently as every six hours, in patients with normal renal function. Concomitant administration of ‘Tiënam’ and probenecid resulted in minimal increases in the plasma levels and plasma half-life of imipenem. The urinary recovery of active (non metabolized) imipenem decreased to approximately 60% of the dose when ‘Tiënam’ was administered with probenecid. When administered alone, imipenem is metabolized in the kidneys by dehydropeptidase-I. Individual urinary recoveries ranged from 5 to 40%, with an average recovery of 15-20% in several studies. Cilastatin: Peak plasma levels of cilastatin, following a 20-minute intravenous infusion of ‘Tiënam’,

ranged from 21 to 26 µg/ml for the 250-mg dose, from 21 to 55 µg/ml for the 500-mg dose and from 56 to 88 µg/ml for the 1000-mg dose. The plasma half-life of cilastatin is approximately one hour. Approximately 70-80% of the dose of cilastatin was recovered unchanged in the urine as the parent drug within 10 hours of administration of ‘Tiënam’. No further cilastatin appeared in the urine thereafter. Approximately 10% was found as the N-acetyl metabolite, which has inhibitory activity against dehydropeptidase comparable to that of the parent drug. Activity of dehydropeptidase-I in the kidney returns to normal levels shortly after the elimination of cilastatin from the blood stream. Concomitant administration of ‘Tiënam’ and probenecid doubled the plasma level and half-life of cilastatin, but had no effect on the percentage of cilastatin recovered from the urine. Intramuscular administration Imipenem: Following intramuscular administration of 500-mg or 750-mg doses of ‘Tiënam’ with Lidocaine HCl (1%), peak plasma levels of imipenem occurred with two hours and averaged 10 and 12 µg/ml, respectively. When compared to intravenous administration of ‘Tiënam’, imipenem was approximately 75% bio-available. The absorption of imipenem from the intramuscular injection site continued for six to eight hours resulting in plasma levels of imipenem which remained above 2 µg/ml for at least six or eight hours, respectively, following a 500-mg or 750-mg dose (see table 5). These are above the MIC90 of clinically important pathogens including gram-negative aerobic and anaerobic rods such as Serratia spp., Acinetobacter spp. and Bacteroides fragilis as well as gram-positive cocci with the exception of enterococci. Intramuscular administration of ‘Tiënam’ 500 mg or 750 mg every 12 hours resulted in slight accumulation of imipenem. Urine levels of imipenem were above 10 µg/ml for 12 hours following intramuscular ‘Tiënam’ 500 mg or 750 mg. Total urinary excretion of imipenem averaged 50% of the dose. Cilastatin: intramuscular administration of ‘Tiënam’

TIENAM - p.9/10 500 mg or 750 mg with Lidocaine HCl (1%) resulted in peak plasma levels of cilastatin, which averaged 24 and 33 µg/ml. Peak plasma levels of cilastatin occurred within one hour. Compared to intravenous administration of ‘Tiënam’, cilastatin was approximately 95% bioavailable. Cilastatin absorption from the intramuscular injection site was essentially complete within four hours. No accumulation of cilastatin was observed following twice daily administration of intramuscular ‘Tiënam’ 500 mg or 750 mg. Total urinary recovery of cilastatin averaged 75% of the intramuscular doses of ‘Tiënam’.

olized in the liver and excreted by the kidneys. Some 90% of a Lidocaine HCl dose is excreted in the form of metabolites, only 10% is excreted unchanged. The major metabolites, monoethyl glycinexylidide and glycinexylidide, also posess pharmacologic activity. The plasma half-life of Lidocaine HCl is 1.5-2 hours; of monoethyl glycinexylidide 2 hours and that of glycinexylidide about 10 hours. 5.3 PRECLINICAL SAFETY DATA No particulars.

6. PHARMACEUTICAL PARTICULARS 6.1 LIST OF EXCIPIENTS Table 5: Intravenous and intramuscular plasma concentra‘Tiënam’ I.V. is buffered with sodium bicarbonate tions of imipenem (µg/ml) to provide solutions in the pH range of 6.5 to 8.5. 750 mg 500 mg Time I.V. I.M. I.V. I.M. There is no significant change in pH when solutions 25 min 57.0 6.7 45.1 6.0 are prepared and used as directed. ‘Tiënam’ I.V. 250 1h 28.1 10.0 21.6 9.4 contains 18.8 mg of sodium (0.8 mmol) and ‘Tiënam’ 2h 12.0 11.4 10.6 9.9 I.V. 500 contains 37.5 mg of sodium (1.6 mmol). 4h 3.4 7.3 2.6 5.6 6h 1.1 3.8 0.6 2.5 ‘Tiënam’ I.M. 500 contains 32 mg of sodium (1.4 mEq.) 12 h ND* 0.8 ND* 0.5 and ‘Tiënam’ I.M. 750 contains 48  mg of sodium * ND: not detectable (