Ampipluss

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMPIPLUS (AMPIPLUS)

Composition:

Active substance: ampicillin/sulbactam;

1 vial contains: 1000 mg of ampicillin (in the form of sodium ampicillin) and 500 mg of sulbactam (in the form of sodium sulbactam).

Pharmaceutical form. Powder for solution for injection or infusion.

Main physicochemical properties: vials containing a crystalline hygroscopic powder of white or almost white color.

Pharmacotherapeutic group. Antibacterial agent for systemic use. Ampicillin and enzyme inhibitor. ATC code J01CR01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The mechanism of action of ampicillin is based on inhibition of bacterial cell wall synthesis (during the growth phase) by blocking penicillin-binding proteins (PBPs), for example transpeptidases. This leads to a bactericidal effect.

Inactivation of ampicillin by certain beta-lactamases is inhibited when ampicillin is used in combination with sulbactam. Sulbactam protects ampicillin from degradation by most beta-lactamases produced by staphylococci, as well as by certain plasmid-encoded beta-lactamases (e.g., TEM, OXA, SHV, CTX‑M) and certain chromosomally encoded beta-lactamases of Gram-negative bacteria. These beta-lactamases are present, for example, in Escherichia coli, species of the genus Klebsiella, Proteus mirabilis, and Haemophilus influenzae. The antimicrobial spectrum of ampicillin is extended to bacteria whose beta-lactamases can be inhibited by sulbactam.

Relationship between pharmacokinetics and pharmacodynamics

Efficacy primarily depends on the duration of time during which the concentration of the active substance (ampicillin) exceeds the minimum inhibitory concentration (MIC) for a specific pathogen.

Mechanisms of resistance

Resistance to ampicillin/sulbactam may be based on the following mechanisms:

° Inactivation by beta-lactamases: ampicillin/sulbactam do not exhibit sufficient activity against bacteria producing beta-lactamases that are not inhibited by sulbactam.

° Reduced affinity of PBPs to ampicillin: acquired resistance to ampicillin/sulbactam in pneumococci and other streptococci is due to alterations in existing PBPs caused by mutation. Methicillin (oxacillin)-resistant staphylococci are resistant because they produce additional PBPs with reduced affinity to ampicillin and all other beta-lactam antibiotics.

° In Gram-negative bacteria, insufficient penetration of ampicillin through the outer cell membrane may result in inadequate inhibition of PBPs.

° Ampicillin may be actively transported out of the cell via efflux pumps.

Partial or complete cross-resistance between ampicillin/sulbactam and penicillins, cephalosporins, and other beta-lactam antibiotic/beta-lactamase inhibitor combinations may occur.

Typically susceptible microorganisms

-Aerobic Gram-positive bacteria: Enterococcus faecalis°, Gardnerella vaginalis°, Staphylococcus aureus (methicillin-susceptible), Streptococcus agalactiae°, Streptococcus pneumoniae°, Streptococcus pyogenes °, Viridans group streptococci°˄.

-Aerobic Gram-negative bacteria: Citrobacter koseri°, Haemophilus influenzae, Moraxella catarrhalis∞, Neisseria gonorrhoeae°.

• Anaerobic bacteria: Bacteroides fragilis°, Fusobacterium nucleatum °, Prevotella spp. °.

Microorganisms that may occasionally develop resistance

-Aerobic Gram-positive bacteria: Enterococcus faecium†, Staphylococcus aureus∋, Staphylococcus epidermidis†, Staphylococcus haemolyticus†, Staphylococcus hominis†.

-Aerobic Gram-negative bacteria: Acinetobacter baumannii, E. coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris.

Naturally resistant microorganisms

-Aerobic Gram-positive bacteria: Staphylococcus aureus (methicillin-resistant).

-Aerobic Gram-negative bacteria: Citrobacter freundii, Pseudomonas aeruginosa, Enterobacter cloacae, Legionella pneumophila, Morganella morganii, Serratia marcescens, Stenotrophomonas maltophilia.

-Other bacteria: Chlamydia spp., Chlamydophila spp., Mycoplasma spp., Ureaplasma urealyticum.

° At the time of publication of this information, updated data were not available. In primary and standard literature and therapeutic recommendations, susceptibility is indicated as likely.

† Resistance rates exceed 50% in at least one region.

˄ Averaged data for a heterogeneous group of streptococcal species. Resistance rates may vary depending on the specific streptococcal species.

∞ No current data available; in studies conducted over 5 years ago, the proportion of resistant strains was reported as ˂ 10%.

∋ In outpatient settings, resistance frequency is approximately 10%.

Clinical breakpoints

Susceptibility testing of ampicillin/sulbactam has been performed using various concentrations of ampicillin in the presence of a constant concentration of 4 mg/L sulbactam. The following clinical breakpoints for minimum inhibitory concentration (EUCAST breakpoints) have been defined for susceptible and resistant pathogens:

Organism	Susceptible	Resistant
Enterobacterales	≤ 8 mg/lN	> 8 mg/lN
Staphylococcus spp. 1)	‑ 1)	‑ 1)
Enterococcus spp.	≤ 4 mg/l	> 8 mg/l
Streptococcus spp. (Groups A, B, C, G)2)	‑ 2)	‑ 2)
Streptococcus pneumoniae2)	‑ 2)	‑ 2)
Haemophilus influenzae	≤ 1 mg/l	> 1 mg/l
Moraxella catarrhalis	≤ 1 mg/l	> 1 mg/l
Gram-negative anaerobic bacteria	≤ 4 mg/l	> 8 mg/l
Gram-positive anaerobic bacteria	≤ 4 mg/l	> 8 mg/l
Non-species-specific quality control parameters 3) *	≤ 2 mg/l	> 8 mg/l

N German National Committee for Antibiotic Susceptibility Testing has established an intermediate range breakpoint for Enterobacteriaceae isolates without resistance mechanisms (I) (wild type): Citrobacter amalonaticus, Citrobacter koseri, Escherichia coli, Escherichia hermannii, Klebsiella spp., Proteus mirabilis, Proteus penneri, Proteus vulgaris, Raoultella spp., Salmonella spp., Shigella spp., Yersinia pseudotuberculosis.

I: > 0.5 ≤ 8 mg/L.

This means that treatment of systemic Enterobacteriaceae infections with ampicillin/sulbactam requires higher dosing (e.g., 3 g intravenously three times daily in patients without modifying factors).

1. For Staphylococcus spp., cefoxitin testing results were used. Methicillin (cefoxitin)-resistant staphylococci are considered resistant regardless of testing.
2. For Streptococcus spp. (groups A, B, C, G) and Streptococcus pneumoniae, penicillin G testing results were used.
3. The susceptibility breakpoint refers to an intravenous daily dose of 3 g administered three times daily; the intermediate breakpoint refers to an intravenous daily dose of 4 g administered three times daily.

* Primarily based on pharmacokinetics of serum levels.

The level of acquired resistance may vary depending on geographical location and time; therefore, especially for the treatment of severe infections, local resistance data for individual species are desirable. If necessary, expert advice should be sought when local resistance levels are such that the benefit of using the drug becomes questionable. During treatment of severe infections or in cases of treatment failure, microbiological diagnosis should be established, including pathogen identification and determination of susceptibility to ampicillin/sulbactam.

Pharmacokinetics.

High serum levels of ampicillin/sulbactam are achieved after both intravenous and intramuscular administration. Pharmacokinetic study results in volunteers show the following serum concentrations as a function of time, dose, and route of administration.

Table 1

Route of administration	Dose	15 min	30 min	1 hour	2 hours	4 hours	6 hours	8 hours
IM	0.25 g sulb. + 0.5 g amp.	6 9	7 12	6 12	3 6	1 2	0.3 0.4	0.1 0.2
IM	0.5 g sulb. + 1 g amp.	8 10	11 16	12 17	8 13	3 4	1 1	0.4 0.6
IV	0.5 g sulb. + 1 g amp.	21 39	15 28	9 14	4 6	1 1	0.4 0.4	0.1 0.2
IV	1 g sulb. + 2 g amp.	51 95	37 65	21 33	9 12	2 3	0.7 1	0.3 0.4

Average serum concentrations (mg/l)

Higher maximum serum levels are achieved after intravenous administration of ampicillin/sulbactam compared to intramuscular administration. The bioavailability of ampicillin/sulbactam after intramuscular injection is nearly complete.

In addition, both ampicillin and sulbactam rapidly distribute into most tissues, body fluids, and secretions.

The elimination half-life of both components is approximately 1 hour in young adults and approximately 2 hours in elderly patients. About 80% of both substances are excreted unchanged in the urine within 8 hours after a single dose of ampicillin/sulbactam. Concomitant administration of sulbactam and ampicillin has not been shown to result in clinically significant deviations from the kinetic parameters of these two substances observed when they are administered separately.

Clinical characteristics.

Indications.

Treatment of infections caused by microorganisms sensitive to the components of the drug:

• infections of the upper and lower respiratory tract, including sinusitis, otitis media, epiglottitis, and bacterial pneumonia;

• urinary tract infections and pyelonephritis;

• intra-abdominal infections, including peritonitis, cholecystitis, endometritis, and pelvic inflammatory disease;

• bacterial septicemia;

• skin, soft tissue, bone, and joint infections;

• gonococcal infections.

Ampipuls may be administered in the perioperative period to reduce the incidence of postoperative infections in patients undergoing abdominal and pelvic surgery where contamination of the abdominal cavity may occur. In cesarean section or termination of pregnancy, Ampipuls may be used prophylactically to reduce the incidence of postoperative sepsis.

It should be noted that ampicillin/sulbactam is not effective against Pseudomonas aeruginosa.

When using Ampipuls, official recommendations regarding the appropriate use of antimicrobial agents should be taken into account.

Contraindications.

Hypersensitivity to the components of the drug.

History of hypersensitivity to penicillins or cephalosporins.

Infectious mononucleosis or lymphatic leukemia (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

The following drug interactions between this medicinal product and other medicinal products are important:

Acetylsalicylic acid, indomethacin, and phenylbutazone delay the elimination of penicillins.

Other antibiotics or chemotherapeutic agents

Sulbactam/ampicillin should not be used concomitantly with other bacteriostatic chemotherapeutic agents or antibiotics such as tetracyclines, erythromycin, sulfonamides, or chloramphenicol, as this may result in reduced efficacy of the drug.

Allopurinol

Patients with gout receiving allopurinol have an increased risk of developing skin reactions when ampicillin/sulbactam is administered concomitantly.

Aminoglycosides

Mixing ampicillin with aminoglycosides in vitro leads to mutual inactivation; if these groups of antibacterial agents are used simultaneously, they should be administered at different sites with an interval of at least 1 hour (see section "Incompatibilities").

Anticoagulants

Parenteral penicillins may cause impairment of platelet aggregation and alteration of prothrombin time. When used concomitantly with anticoagulants, these effects may be additive.

Methotrexate

Concomitant use of methotrexate with penicillins has led to decreased methotrexate clearance and methotrexate toxicity. Close monitoring of patients is required. It may be necessary to increase the dose of calcium folinate and extend its duration of administration.

Probenecid

Concomitant use of probenecid results in increased and prolonged serum levels of ampicillin and sulbactam, higher biliary concentrations of ampicillin, prolonged elimination half-life, and increased risk of toxicity due to inhibition of renal excretion (tubular secretion).

Hormonal contraceptives

In isolated cases, therapy with aminopenicillins may compromise the effectiveness of hormonal contraceptives. Therefore, additional non-hormonal contraceptive methods are recommended.

Effect on laboratory test results

A false-positive result for glucosuria may occur when testing for glucose in urine (using Benedict's, Fehling's, or Clinitest reagents). In such cases, glucose should be determined enzymatically. May affect urobilinogen test results.

When ampicillin was administered to pregnant women, a transient decrease in plasma levels of conjugated estrogens, estriol glucuronide, conjugated estrone, and estradiol was observed. Similar effects are possible with the use of Ampipuls.

Special precautions for use.

In patients with established allergic reactions such as hay fever, urticaria, or bronchial asthma, the risk of hypersensitivity reactions is increased.

Severe hypersensitivity reactions, sometimes fatal (anaphylactic reactions), have been observed in patients receiving penicillins, including ampicillin/sulbactam, administered intramuscularly or intravenously. Such reactions occur more frequently in patients with hypersensitivity to penicillins, as well as cephalosporins and/or multiple allergens in their medical history. In the event of an allergic reaction, antibiotic therapy should be discontinued and appropriate therapeutic measures initiated. Acute, severe hypersensitivity reactions require immediate treatment with epinephrine, administration of oxygen, intravenous corticosteroids, and ensuring airway patency, with mechanical ventilation via intubation if necessary.

As a precautionary measure, during therapy lasting more than one week, monitoring of liver enzyme levels and carbohydrate metabolism should be performed, although with the use of Ampiplyus in patients with diabetes mellitus, no clinically significant effects on glucose availability have been observed.

Periodic monitoring of complete blood count and renal function should be performed during prolonged therapy (more than 14 days). This monitoring is particularly important in newborns, especially premature infants and infants.

As with any antibiotic therapy, continuous monitoring for signs of overgrowth of non-susceptible microorganisms, including fungi, is necessary. Caution should be exercised when prescribing the antibiotic in combination with glucocorticoids, as this may increase the risk of superinfection due to reduced resistance to infections. If superinfection occurs, the drug should be discontinued and appropriate therapy initiated.

Severe skin reactions such as toxic epidermal necrolysis, Stevens–Johnson syndrome, exfoliative dermatitis, erythema multiforme, and acute generalized exanthematous pustulosis have been reported in patients receiving ampicillin/sulbactam. If a patient develops a severe skin reaction, treatment with Ampiplyus should be discontinued and appropriate therapy initiated (see section "Adverse reactions").

Treatment with ampicillin/sulbactam may affect the following laboratory parameters: non-enzymatic methods for determining glucose in urine may yield false-positive results. Treatment may also affect urobilinogen test results. Following administration of ampicillin in pregnant women, a transient decrease in plasma concentrations of various estrogens has been observed. This effect may also occur during treatment with Ampiplyus.

Diarrhea caused by Clostridium difficile (CDAD) has been reported with the use of nearly all antibacterial agents, including Ampiplyus, with severity ranging from mild diarrhea to fatal colitis. Antibiotic treatment alters the normal flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hyper-toxin-producing strains of C. difficile are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy, potentially requiring colectomy. CDAD should be considered in all patients who develop diarrhea after antibiotic use. A careful medical history is essential, as cases of CDAD have been reported up to 2 months after antibiotic administration.

In cases of severe and persistent diarrhea, treatment with Ampiplyus should be discontinued immediately and appropriate therapy initiated (e.g., oral vancomycin 4×250 mg daily). Medications that inhibit intestinal peristalsis are contraindicated.

Before initiating treatment for gonorrhea, when there is suspicion of concomitant syphilis, a dark-field examination should be performed. Thereafter, serological tests should be conducted monthly for at least 4 months.

During prolonged therapy, monitoring of liver, kidney, and hematopoietic system function is recommended, especially in newborns (particularly premature infants) and infants.

To avoid the development of resistance and adverse effects, the combination of ampicillin and sulbactam should be used only when the efficacy of either agent alone is insufficient.

Ampicillin/sulbactam has been associated with drug-induced liver injury, including cholestatic hepatitis and jaundice. Therefore, patients should be advised to consult their physician if symptoms or signs of liver disease develop (see section "Adverse reactions").

Each vial of Ampiplyus 1.5 g contains approximately 5 mmol of sodium. This should be taken into account in patients on a sodium-restricted diet (low sodium/salt intake).

Patients with infectious mononucleosis or lymphatic leukemia should not be treated with Ampiplyus for concomitant bacterial infections, as such patients have a higher tendency to develop rash-like skin reactions.

Use during pregnancy or breastfeeding.

Pregnancy

Current research data have not demonstrated any harmful effects on the fetus. Sulbactam crosses the placental barrier. Limited experience with the use of ampicillin/sulbactam has been obtained in 244 women during term or preterm labor. However, the safety of ampicillin/sulbactam in pregnant or breastfeeding women has not been established. Therefore, ampicillin/sulbactam should be used during pregnancy only if the potential benefit outweighs the possible risk.

Breastfeeding

Ampicillin (approximately 0.11 to 3 mg/L) and sulbactam (approximately 0.13 to 2.8 mg/L) pass into breast milk in low concentrations. Administration of ampicillin/sulbactam to breastfeeding women may cause adverse reactions in infants, such as diarrhea. Ampicillin/sulbactam may be used during breastfeeding only if the potential benefit outweighs the possible risk.

Fertility

Animal reproductive studies with ampicillin/sulbactam have shown no evidence of impaired fertility or fetal harm.

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted to evaluate the effect of Ampiplyus on reaction speed during driving or operating machinery. Nevertheless, patients should be informed that rare adverse effects such as dizziness or increased fatigue may affect reaction speed.

Administration and Dosage

Ampiplyus should be administered intramuscularly or intravenously (as a bolus injection or infusion).

To prepare the medication for use, it should be reconstituted with sterile water for injection or another compatible diluent. After adding the diluent, wait several minutes until the foam completely disappears, then visually assess the completeness of dissolution.

For Ampiplyus 1.5 g, reconstitute with 3.2 mL of water for injection (or another compatible diluent) accordingly. Administer as a bolus injection (over at least 3 minutes). With greater dilution, the dose may be administered as an intravenous infusion (over 15–30 minutes).

When administered intramuscularly, the drug should be injected deeply into the muscle. If injections are painful, the powder may be reconstituted using 0.5% sterile lidocaine hydrochloride injection solution or another suitable local anesthetic. Consider the contraindications specified in the medical instructions for the respective medicinal product.

If 0.5% sterile lidocaine hydrochloride injection solution or another local anesthetic is used for reconstitution of the powder, take into account the contraindications listed in the medical instructions for the respective medicinal product.

Maximum final concentration of ampicillin/sulbactam – 250 mg/125 mg per 1 mL.

Treatment of infections caused by microorganisms sensitive to sulbactam and ampicillin

Use in adults

Prior to initiating therapy with Ampiplyus, hypersensitivity to the drug and lidocaine should be assessed in the patient by a skin test.

Depending on the severity of infection, the daily dose of Ampiplyus ranging from 1.5 g to 12 g should be administered in divided doses every 6–8 hours (every 12 hours in less severe infections); the maximum daily dose should not exceed 12 g of Ampiplyus (4 g of sulbactam).

Severity of infection	Daily dose of Ampiplus ampicillin/sulbactam (g)
Mild Moderate Severe	1.5–3 (from 1+0.5 to 2+1) up to 6 (4+2) up to 12 (8+4)

Use in children, infants, and newborns

For children, infants, and newborns (from 1 week of age), the usual daily dose is 150 mg/kg body weight (corresponding to 100 mg/kg/day ampicillin and 50 mg/kg/day sulbactam), administered in divided doses every 6 or 8 hours.

For newborns during the first week of life (especially premature infants), the drug is generally administered at a dose of 75 mg/kg/day (corresponding to 50 mg/kg/day ampicillin and 25 mg/kg/day sulbactam) in divided doses every 12 hours.

For surgical infection prophylaxis, the dose of Ampiplus is 1.5–3 g, administered during induction of anesthesia to allow sufficient time for achieving effective serum and tissue concentrations during surgery. The dose may be repeated every 6–8 hours; however, use of Ampiplus should generally be discontinued within 24 hours after surgery, except when the drug is administered for therapeutic purposes.

For treatment of uncomplicated gonorrhea, Ampiplus may be administered as a single 1.5 g intravenous or intramuscular dose. To prolong plasma concentrations of sulbactam and ampicillin, probenecid should be administered concomitantly at a dose of 1 g orally.

Use in patients with renal impairment

In patients with severe renal impairment (creatinine clearance < 30 mL/min), elimination of both sulbactam and ampicillin is similarly delayed, so their plasma ratio remains unchanged. For such patients, the dosing intervals of Ampiplus should be prolonged according to standard ampicillin dosing guidelines.

Table 2

Creatinine clearance (mL/min)	Dosing interval
> 30	6-8 hours
15-29	12 hours
5-14	24 hours
< 5	48 hours

Patients undergoing dialysis

Both sulbactam and ampicillin are eliminated to a similar extent by hemodialysis. Therefore, Ampiplyus should be administered immediately after dialysis and then, until the start of the next dialysis, administered at 48-hour intervals.

Use in patients with hepatic impairment

Dosage adjustment is not required for patients with impaired liver function.

Use in elderly patients

In the absence of renal impairment, dosage adjustment of Ampiplyus is not required for elderly patients.

Treatment duration depends on the severity of infection and is usually 5–14 days; however, in more severe cases, treatment may be prolonged or additional ampicillin may be prescribed. Generally, treatment should continue for an additional 48 hours after normalization of body temperature and disappearance of other signs and symptoms of bacterial infection.

The treatment duration for infections caused by hemolytic streptococci should last at least 10 days in order to prevent rheumatic fever and glomerulonephritis.

Reconstitution instructions

The concentrated solution for intramuscular administration should be used within 1 hour after reconstitution.

The shelf life of the solution for intravenous infusion, depending on the type of diluent used, is indicated below:

Table 3

Solvent	Concentration	Temperature	Time
0.9% sodium chloride solution	45 mg/ml	25 °C	8 hours
	45 mg/ml	4 °C	48 hours
	30 mg/ml	4 °C	72 hours
5% Dextrose solution	15–30 mg/ml	25 °C	2 hours
	3 mg/ml	25 °C	4 hours
	30 mg/ml	4 °C	4 hours
5% Dextrose in 0.45% sodium chloride solution	3 mg/ml	25 °C	3 hours
	15 mg/ml	4 °C	4 hours
Lactated Ringer's solution	45 mg/ml	25 °C	7 hours
	45 mg/ml	4 °C	24 hours

Children.

Use in children from birth.

Overdose.

Available data on acute toxicity of ampicillin/sulbactam in humans are limited. It could be expected that overdose of this medicinal product will lead to manifestations corresponding to the adverse effect profile of Ampiplyus (see section «Adverse reactions» below). It is expected that in case of overdose, adverse reactions will be recorded more frequently and will be of a more severe degree. Very high doses of beta-lactam antibiotics may lead to epileptic seizures. Since both ampicillin and sulbactam are eliminated from the bloodstream by hemodialysis, performing hemodialysis may enhance the elimination of the medicinal product from the body in cases of overdose in patients with impaired renal function. Anaphylactic shock, which is not poisoning, is very rare but always life-threatening.

Treatment

To control seizures caused by overdose, diazepam should be administered. In case of anaphylactic shock, appropriate treatment should be initiated immediately.

Adverse Reactions

When administering sodium ampicillin/sodium sulbactam intramuscularly (i.m.) or intravenously (i.v.), adverse reactions may occur that were previously observed during ampicillin monotherapy.

All listed adverse reactions are classified according to MedDRA organ system classes. Within each category, adverse reactions (ARs) are listed in decreasing order of severity. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations

Frequency not known: pseudomembranous colitis.

Blood and lymphatic system disorders

Common: anaemia, thrombocytopenia, eosinophilia.
Uncommon: leukopenia, neutropenia.
Very rare: bone marrow depression, pancytopenia.
Frequency not known: haemolytic anaemia, agranulocytosis, thrombocytopenic purpura.

Immune system disorders

Frequency not known: hypersensitivity reactions, anaphylactic shock, anaphylactoid reaction, anaphylactic reaction, anaphylactoid shock, laryngeal oedema, serum sickness.

Nervous system disorders

Uncommon: headache.
Frequency not known: seizures, dizziness, somnolence, sedative effect.

Cardiac disorders

Frequency not known: tachycardia.

Vascular disorders

Common: phlebitis.

Respiratory, thoracic and mediastinal disorders

Frequency not known: respiratory distress syndrome.

Gastrointestinal disorders

Common: diarrhoea.
Uncommon: vomiting.
Rare: abdominal pain, nausea, glossitis, flatulence.
Frequency not known: enterocolitis, stomatitis, tongue discoloration, melena, dyspepsia, tongue oedema.

Hepatobiliary disorders

Common: hyperbilirubinaemia (see section "Special precautions for use").
Frequency not known: cholestatic hepatitis, cholestasis, hepatic cholestasis, abnormal liver function, jaundice (see section "Special precautions for use").

Skin and subcutaneous tissue disorders

Uncommon: rash (exanthema), pruritus.
Rare: erythema.
Frequency not known: Stevens–Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, acute generalized exanthematous pustulosis (AGEP), exfoliative dermatitis, angioneurotic oedema, urticaria, dermatitis, maculopapular rash, morbilliform rash, hypersensitivity, vasculitis (see section "Special precautions for use").

Renal and urinary disorders

Frequency not known: tubulointerstitial nephritis.

General disorders and administration site conditions

Common: injection site pain (after intramuscular administration).
Uncommon: fatigue, malaise, mucosal inflammation.
Rare: hyperthermia.
Frequency not known: injection site reaction, chest pain, facial oedema.

Investigations

Common: increased alanine aminotransferase (ALT) levels, increased aspartate aminotransferase (AST) levels (see section "Special precautions for use").
Very rare: prolonged coagulation time*, prolonged prothrombin time*.
Frequency not known: decreased blood pressure.

* These symptoms are reversible.

Pseudomembranous colitis

In cases of severe and persistent diarrhoea, antibiotic-associated pseudomembranous colitis, which may be life-threatening, should be considered. In such cases, treatment with Ampiplus should be discontinued immediately and appropriate therapy initiated (e.g., vancomycin 250 mg orally four times daily). The use of drugs that reduce peristalsis is contraindicated.

Hypersensitivity reactions

If symptoms of allergic reactions occur (e.g., rash, pruritus, urticarial exanthema, maculopapular rash, morbilliform exanthema), the drug should be discontinued.

Emergency medical intervention may be required if signs of a severe acute hypersensitivity reaction occur (facial swelling, tongue swelling, internal laryngeal swelling with airway narrowing, severe skin reactions such as erythema multiforme, Stevens–Johnson syndrome or toxic epidermal necrolysis (Lyell’s syndrome), tachycardia, dyspnoea, drug fever, eosinophilia, serum sickness, haemolytic anaemia, allergic vasculitis and nephritis, hypotension, anaphylactoid reaction, anaphylactic shock).

Cross-reactivity between skin fungi and penicillin may exist; therefore, hypersensitivity reactions cannot be excluded in individuals with current or past fungal skin infections, even upon first exposure to penicillin.

A typical morbilliform exanthema occurring 5–11 days after initiation of ampicillin therapy does not preclude further treatment with penicillin derivatives.

Seizures

Seizures may occur with all penicillins at very high serum concentrations. Therefore, the drug should be used with caution, especially in patients with impaired renal function (see section "Dosage and administration").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities.

Ampiplus must not be mixed with blood products or protein hydrolysates. Due to chemical incompatibility between penicillins and aminoglycosides, which leads to inactivation of aminoglycosides, Ampiplus must not be mixed with aminoglycosides in the same syringe or infusion solution. These two substances should be administered at different sites, with an interval of at least 1 hour.

The following are also incompatible and therefore must be administered separately: metronidazole, injectable tetracycline derivatives such as oxytetracycline, rolitetracycline and doxycycline, as well as thiopental sodium, prednisolone, 2% procaine, succinylcholine chloride and noradrenaline. Visible signs of incompatibility include precipitation, turbidity, or colour change.

Packaging.

Vial; 1, 10 or 25 vials per cardboard box.

Prescription category. Prescription only.

Manufacturer.

ANTIBIOTICE SA
ANTIBIOTICE SA

Manufacturer's address and location of business activity.

1 Valea Lupului Street, Iasi 707410, Romania
1, Valea Lupului Street, 707410, Iasi, Romania