Piperacillin / Tazobactam 2 g / 0.25 g powder for solution for injection or infusion

1. Name Of The Medicinal Product

Piperacillin/Tazobactam 2 g / 0.25 g powder for solution for injection or infusion

2. Qualitative And Quantitative Composition

Each vial contains piperacillin sodium corresponding to 2g piperacillin and tazobactam sodium corresponding to 0.25g tazobactam.

One vial of powder for solution for injection/infusion contains 4.7 mmol (108mg) of sodium.

3. Pharmaceutical Form

Powder for solution for injection or infusion.

White to off-white powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Piperacillin/Tazobactam is indicated for treatment of the moderate to severe systemic and/or local bacterial infections in which beta-lactamase producing bacteria are suspected or have been detected, such as:

Adults/ Adolescents and the Elderly

- Nosocomial pneumonia; - Complicated urinary tract infections (including pyelonephritis);

- Intra-abdominal infections;

- Skin and soft tissue infections;

- Bacterial infections in neutropenic patients.

Children (2 to 12 years)

Bacterial infections in neutropenic children.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Piperacillin/Tazobactam may be given by slow intravenous injection (over at least 3-5 minutes) or by slow intravenous infusion (over 20-30 minutes).

For reconstitution instructions, see section 6.2 and 6.6.

The treatment of mixed infections caused by piperacillin susceptible organisms and beta-lactamase producing organisms susceptible to piperacillin/tazobactam generally do not require the addition of another antibiotic.

In patients with nosocomial pneumonia and infections in neutropenic patients piperacillin/tazobactam can be used with an aminoglycoside. If the use of an aminoglycoside is needed, with piperacillin/tazobactam, both piperacillin/tazobactam and the aminoglycoside must be used in completely therapeutic doses.

Neutropenic patients with signs of infection (e.g. fever) should receive immediate empirical antibiotic therapy before laboratory results are available.

Adults and Children Over 12 Years, Each with Normal Renal Function

The usual dosage for adults and children over 12 years is 4.5g Piperacillin/Tazobactam (4g piperacillin / 500mg tazobactam) given every 8 hours.

The total daily dose of Piperacillin/Tazobactam depends on the severity and localisation of the infection and can vary from 2.25g (2g piperacillin / 250mg tazobactam) to 4.5g (4g piperacillin / 500mg tazobactam) administered every 6 or 8 hours.

In neutropenia the recommended dose is 4.5g Piperacillin/Tazobactam (4g piperacillin / 500mg tazobactam) given every 6 hours in combination with an aminoglycoside.

Elderly with Normal Renal Function

Piperacillin/Tazobactam may be used at the same dose levels as adults except in cases of renal impairment (see below):

Renal Insufficiency in Adults, the Elderly and Children (over 40 Kg) Receiving the Adult Dose

In patients with renal insufficiency, the intravenous dose should be adjusted to the degree of actual renal impairment. The suggested daily doses are as follows:

Creatinine clearance (ml/min)	Recommended Piperacillin/Tazobactam dosage
Total	Divided doses
20 - 80	12/1.5g /day	4000/500 mg q 8H
< 20	8/1g /day	4000/500 mg q 12H

For patients on haemodialysis, the maximum daily dose is 8g/1g piperacillin/tazobactam. In addition, because haemodialysis removes 30%-50% of piperacillin in 4 hours, one additional dose of 2g/250mg piperacillin/tazobactam should be administered following each dialysis period.

For patients with renal failure and hepatic insufficiency, measurement of serum levels of Piperacillin/Tazobactam will provide additional guidance for adjusting dosage.

Children aged 2 to 12 years with normal renal function

Piperacillin/Tazobactam is only recommended for the treatment of children with neutropenia.

Neutropenia

For children weighing less than 40 kg the dose should be adjusted to 90mg/kg (80mg piperacillin / 10mg tazobactam) administered every 6 hours, in combination with an aminoglycoside, not exceeding 4.5g (4g piperacillin / 500mg tazobactam) every 6 hours.

Renal Insufficiency in Children Aged 2-12 Years (or bodyweight less than 40 kg)

In children with renal insufficiency the intravenous dosage should be adjusted to the degree of actual renal impairment as follows:

Creatinine clearance (ml/min)	Recommended piperacillin/tazobactam dosage	Frequency	Maximum daily dosage
>40	No adjustment necessary
20-39	90 mg (piperacillin/tazobactam 80/10 mg) /kg	q 8H	12/1.5g /day
< 20	90mg (piperacillin/tazobactam 80/10 mg) /kg	q 12H	8/1g /day

For children weighing < 50 kg on haemodialysis the recommended dose is 45 mg (40mg piperacillin /5mg tazobactam) /kg every 8 hours.

The above dosage modifications are only an approximation. Each patient must be monitored closely for signs of drug toxicity. Drug dose and interval should be adjusted accordingly.

Children under 2 years:

Piperacillin/Tazobactam is not recommended for use in children below 2 years old due to insufficient data on safety.

Hepatic Impairment

No dose adjustment is necessary.

Duration of Therapy

The duration of therapy should be guided by the severity of the infection and the patient's clinical and bacteriological progress.

In acute infections, treatment with Piperacillin/Tazobactam should be continued for 48 hours beyond the resolution of clinical symptoms or the fever.

4.3 Contraindications

Patients with a history of hypersensitivity to the active substances, to other beta-lactams (e.g. penicillins and cephalosporins) or to any other beta-lactamase inhibitor.

4.4 Special Warnings And Precautions For Use

Warnings

Serious and occasionally fatal hypersensitivity (anaphylactic / anaphylactoid [including shock]) reactions have been reported in patients receiving therapy with penicillins including piperacillin / tazobactam. These reactions are more likely to occur in persons with a history of sensitivity to multiple allergens.

There have been reports of patients with a history of penicillin hypersensitivity who have experienced severe reactions, when treated with cephalosporin. If an allergic reaction occurs during therapy with piperacillin / tazobactam, the antibiotic should be discontinued. Serious hypersensitivity reactions may require adrenaline and other emergency measures.

Before initiating therapy with piperacillin / tazobactam, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens.

In case of severe, persistent diarrhoea, the possibility of antibiotic-induced, life threatening pseudomembranous colitis must be taken into consideration. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment. Therefore, piperacillin / tazobactam must be discontinued immediately in such cases, and suitable therapy should be initiated.

Precautions

Leukopenia and neutropenia may occur, especially during prolonged therapy. Therefore, periodic assessment of a full blood count should be performed.

Periodic assessment of organ system functions including renal and hepatic during prolonged therapy is advisable.

Bleeding manifestations have occurred in some patients receiving β-lactam antibiotics. These reactions have sometimes been associated with abnormalities of coagulation tests such as clotting time, platelet aggregation and prothrombin time, and are more likely to occur in patients with renal failure. If bleeding manifestations occur, the antibiotic should be discontinued and appropriate therapy instituted.

The possibility of the emergence of resistant organisms, which might cause superinfections, should be kept in mind, particularly during prolonged treatment. Microbiological follow-up may be required to detect any important superinfection. If this occurs, appropriate measures should be taken.

Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously.

This medicinal product contains 4.7 mmol (108 mg) of sodium per vial of powder for solution for injection or infusion. To be taken into consideration by patients on a controlled sodium diet

Hypokalaemia may occur in patients with low potassium reserves or who are receiving concomitant medications that may lower potassium levels; periodic electrolyte determinations should be performed in such patients. Modest elevation of indices of liver function may be observed.

Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients (see also section 4.8).

Until further experience is available, piperacillin/ tazobactam should not be used in children who do not have neutropenia.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction with probenecid:

Concurrent administration of probenecid and piperacillin/tazobactam produced a longer half-life and lower renal clearance for both piperacillin and tazobactam. However, peak plasma concentrations of either drug are unaffected.

Interaction with antibiotics:

No clinically relevant adverse pharmacokinetic interaction with tobramycin or vancomycin has been observed in healthy adults with a normal renal function. The clearance of tobramycin and gentamicin was enhanced in patients with severe renal dysfunction using piperacillin/tazobactam. In these patients mixing of piperacillin/tazobactam formulation with tobramycin and gentamicin was excluded.

For information related to administration of piperacillin/tazobactam with aminoglycosides please refer to section 6.2.

Interaction with anticoagulants:

During simultaneous administration of heparin, oral anticoagulants and other drugs, which may affect the blood coagulation system including thrombocyte function, appropriate coagulation tests should be performed more frequently and monitored regularly.

Interaction with vecuronium:

Piperacillin when used concomitantly with vecuronium has been implicated in the prolongation of the neuromuscular blockade of vecuronium. Due to their similar mechanism of action, it is expected that the neuromuscular blockade produced by any of the non-depolarising muscle relaxants could be prolonged in the presence of piperacillin. This should be taken into account when piperacillin/tazobactam is used peri-operatively.

Interaction with methotrexate:

Piperacillin may reduce the excretion of methotrexate. Serum levels of methotrexate should be monitored in patients on methotrexate therapy.

Interaction with laboratory test results:

The administration of piperacillin / tazobactam may result in a false-positive reaction for glucose in the urine using a copper-reduction method. It is recommended that glucose tests based on enzymatic glucose oxidase reaction be used.

There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving piperacillin-tazobactam injection who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving piperacillin-tazobactam should be interpreted cautiously and confirmed by other diagnostic methods.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate and well-controlled studies with piperacillin/tazobactam combination or with piperacillin or tazobactam alone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Piperacillin and tazobactam cross the placenta. Piperacillin/tazobactam should only be used during pregnancy if clearly indicated.

Lactation

Piperacillin is excreted in low concentrations in breast milk. Tazobactam concentrations in human milk have not been studied. The effect on the suckling infant is unknown. Women who are breast feeding should be treated only if clearly indicated. Diarrhoea and fungal infections of the mucous membranes as well as sensitisation could occur in the breast-fed infant.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

However, side effects may occur (see also section 4.8), which may influence the ability to drive and use machines.

4.8 Undesirable Effects

Undesirable effects are listed by frequency as follows: Very common (

The most commonly reported adverse reactions are diarrhoea, nausea, vomiting, and rash, each having a frequency of

Organ System	Common (>1/100, <1/10)	Uncommon (>1/1,000, <1/100)	Rare (>1/10,000, <1/1,000)	Very rare (<1/10,000), including isolated reports
Infections and infestations:		Candidal superinfection
Blood and lymphatic system disorders:		leucopenia, neutropenia, thrombocytopenia	anaemia, bleeding manifestations(including purpura, epistaxis, bleeding time prolonged) eosinophilia, haemolytic anaemia	agranulocytosis, Coombs direct test positiv, pancytopenia, prolonged partial thromboplastin time, prothrombin time prolonged, thrombocytosis
Immune system disorders:		hypersensitivity reaction	anaphylaxia/ anaphylactoid reaction (including shock)
Metabolism and nutrition disorders				hypoalbuminemia, hypoglycemia, hypoproteinemia, hypokalaemia
Nervous system disorders		headache, insomnia	Muscular weakness, hallucination, convulsion
Vascular disorders		hypotension, phlebitis, thrombophlebitis	Flushing
Gastrointestinal disorders	diarrhoea, nausea, vomiting	constipation, dyspepsia, jaundice, stomatitis	abdominal pain, pseudomembra-nous colitis, dry mouth
Hepatobiliary disorders		alanine aminotransferase increased, aspartate aminotransferase increased	Bilirubin increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, hepatitis
Skin and subcutaneous tissue disorders	Rash including maculopapular rash	pruritus, urticaria, erythema	bullous dermatitis, erythema multiforme, increased sweating, exanthema, eczema	Stevens-Johnson syndrome, toxic epidermal necrolysis
Musculoskeletal, connective tissue and bone disorders			Arthralgia, myalgia
Renal and urinary disorders		blood creatinine increased	interstitial nephritis, renal failure	blood urea nitrogen increased
General disorders and administration site conditions		fever, injection site reaction	rigors, tiredness, oedema

The administration of high doses of beta-lactams, particularly in patients with renal insufficiency, can lead to encephalopathies (consciousness fluctuation, myoclonus and convulsions).

Piperacillin therapy has been associated with an increased incidence of fever and rash in cystic fibrosis patients.

4.9 Overdose

Symptoms

There have been post-marketing reports of overdose with piperacillin/tazobactam. The majority of those events experienced including nausea, vomiting, and diarrhoea have also been reported with the usual recommended dosages. Patients may experience neuromuscular excitability or convulsions if higher than recommended doses are given intravenously (particularly in the presence of renal failure).

Treatment of Intoxication

In the event of an overdose, piperacillin/tazobactam treatment should be discontinued.

No specific antidote is known.

Treatment should be supportive and symptomatic according to the patient's clinical presentation. In the event of an emergency, all required intensive medical measures are indicated as in the case of piperacillin.

Excessive serum concentrations of either piperacillin or tazobactam may be reduced by haemodialysis (for more details, see section 5.2).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Combinations of penicillins, including beta-lactamase inhibitors

ATC classification: J01CR05

Mechanism of action:

Piperacillin, a broad spectrum, semisynthetic penicillin active against many gram-positive and gram-negative aerobic and anaerobic bacteria, exerts bactericidal activity by inhibition of both septum and cell wall synthesis. Tazobactam, a triazolylmethyl penicillanic acid sulphone, is a potent inhibitor of many β-lactamases, in particular the plasmid mediated enzymes which commonly cause resistance to penicillins and cephalosporins including third-generation cephalosporins. The presence of tazobactam in the piperacillin/tazobactam formulation enhances and extends the antibiotic spectrum of piperacillin to include many β-lactamase producing bacteria normally resistant to it and other β-lactam antibiotics. Thus, piperacillin/tazobactam combines the properties of a broad spectrum antibiotic and a β-lactamase inhibitor.

PK/PD relationship:

Similar to other beta-lactam antimicrobial agents, the time that the plasma concentration of

piperacillin exceeds the MIC (%T >MIC) of the infecting organism has been shown to best

correlate with efficacy.

Mechanism of resistance

The presence of tazobactam expands the spectrum of activity of piperacillin to include micro-organisms that would otherwise, due to the formation of beta-lactamase, be resistant to piperacillin and other beta-lactam antibiotics.

In vitro investigation has demonstrated that the type I beta-lactamase inducing ability of tazobactam is insignificant with regard to Gram-negative bacteria.

In vitro studies have demonstrated a synergetic effect of piperacillin/tazobactam and aminoglycosides against Pseudomonas aeruginosa and other bacteria, including beta-lactamase producing strains

Breakpoints

The minimum inhibitory concentration (MIC) breakpoints separating susceptible, intermediately susceptible and resistant organisms have been defined as follows:

EUCAST clinical MIC breakpoints 2008 (version 1.2):

For susceptibility testing purposes, the concentration of tazobactam is fixed at 4 mg/L

Pathogen	Species-related breakpoints (S</R>)
Enterobacteriaceae	8/16
Pseudomonas	16/16
Gram-negative and Gram-positive anaerobes	8/16
Non-species related breakpoints	4/16

The susceptibility of streptococci is inferred from the penicillin susceptibility.

The susceptibility of staphylococci is inferred from the oxacillin susceptibility.

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species

Aerobic Gram-positive micro-organisms Enterococcus faecalis Listeria monocytogenes Staphylococcus aureus (methicillin- susceptible) Coagulase-negative staphylococci (methicillin- susceptible) Streptococcus agalctiae Streptococcus pneumoniae* (penicillin-susceptible) Streptococcus pyogenes* and other beta-hemolytic streptococci

Aerobic Gram-negative micro-organisms Citrobacter koseri Haemophilus influenzae* Haemophilus spp. Moraxella catarrhalis Proteus mirabilis

Anaerobic Gram-positive micro-organisms Clostridium spp. Eubacterium spp. Peptococcus spp. Peptostreptococcus spp.   Anaerobic Gram-negative micro-organisms Bacteroides fragilis * Bacteroides fragilis group Fusobacterium spp. Porphyromonas spp. Prevotella spp. *

Species for which resistance may be a problem

Aerobic Gram-positive micro-organisms Enterococcus avium $ Enterococcus faecium + $ Propionibacterium acnes $ Streptococcus pneumoniae* (intermediate penicillin-susceptibility) Viridans streptococci Aerobic Gram-negative micro-organisms Acinetobacter spp. + $ Burkholderia cepacia Citrobacter freundii Enterobacter spp. Escherichia coli* Klebsiella spp. Proteus, indole positive Pseudomonas aeruginosa * Pseudomonas spp. * Pseudomonas stutzeri $ Serratia spp.   Anaerobic Gram-negative micro-organisms Bacteroides spp. *

Inherently resistant organisms Aerobic Gram-positive micro-organisms Corynebacterium jeikeium Staphylococcus aureus (methicillin-resistant) Coagulase-negative staphylococci (methicillin-resistant) Strptococcus pneumoniae (penicillin resistant) Aerobic Gram-negative micro-organisms Legionella spp. Stenotrophomonas maltophilia + $

* Clinical effectiveness against this has been demonstrated in the registered indications.

^$ species showing natural intermediate susceptibility

⁺ species for which high resistance rates ( more than 50%) have been observed in one or more areas/countries /regions within the EU

5.2 Pharmacokinetic Properties

Distribution

Peak piperacillin and tazobactam plasma concentrations are attained immediately after completion of an intravenous infusion or injection. Piperacillin plasma levels produced when given with tazobactam are similar to those attained when equivalent doses of piperacillin are administered alone.

There is a greater proportional (approximately 28%) increase in plasma levels of piperacillin and tazobactam with increasing dose over the dosage range of 250mg tazobactam/2g piperacillin to 500mg tazobactam/4g piperacillin.

Both piperacillin and tazobactam are 20 to 30% bound to plasma proteins. The protein binding of either piperacillin or tazobactam is unaffected by the presence of the other compound. Protein binding of the tazobactam metabolite is negligible.

Piperacillin and tazobactam are widely distributed in tissue and body fluids including intestinal mucosa, gall bladder, lung, bile and bone.

Biotransformation

Piperacillin is metabolised to a minor microbiologically active desethyl metabolite. Tazobactam is metabolised to a single metabolite, which has been found to be micro-biologically inactive.

Elimination

Piperacillin and tazobactam are eliminated by the kidney via glomerular filtration and tubular secretion.

Piperacillin is excreted rapidly as unchanged drug with 68% of the administered dose appearing in the urine. Tazobactam and its metabolite are eliminated primarily by renal excretion with 80% of the administered dose appearing as unchanged drug and the remainder as the single metabolite. Piperacillin, tazobactam, and desethyl piperacillin are also secreted into the bile.

Following single or multiple doses of piperacillin / tazobactam to healthy subjects, the plasma half-life of piperacillin and tazobactam ranged from 0.7 to 1.2 hours and was unaffected by dose or duration of infusion. The elimination half-lives of both piperacillin and tazobactam are increased with decreasing renal clearance.

There are no significant changes in piperacillin pharmacokinetics due to tazobactam. Piperacillin appears to reduce the rate of elimination of tazobactam.

Impaired Renal Function

Piperacillin and tazobactam are haemodialysable: 31% (piperacillin) and 39% (tazobactam) of administered doses are filtrated. During peritoneal dialysis, 5% of administered piperacillin and 12% of administered tazobactam are found in the dialysis liquid. Patients treated by chronic ambulatory peritoneal dialysis should receive the same dose as non dialysed patients with severe renal insufficiency.

Impaired Liver Function

Plasma concentrations of piperacillin and tazobactam are prolonged in hepatically impaired patients. The half-life of piperacillin and of tazobactam increases by approximately 25% and 18%, respectively, in patients with hepatic cirrhosis compared to healthy subjects. However, dosage adjustments in patients with hepatic impairment are not necessary.

Paediatric patients

The pharmacokinetics of piperacillin/tazobactam has been studied in paediatric patients with intra-abdominal infections and other kind of infections. In every age group, renal fraction of elimination of piperacillin and tazobactam was approximately 70% and 80%, respectively, like in adults.

Mean pharmacokinetic parameters of piperacillin/tazobactam of paediatric patients of different age groups.

	Piperacillin	Tazobactam
Age group	Half-life	Clearance (ml/min/kg)	Half-life	Clearance (ml/min/kg)
2-5 years	0.7	5.5	0.8	5.5
6-12 years	0.7	5.9	0.9	6.2

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity and genotoxicity. Carcinogenicity studies have not been conducted with piperacillin/tazobactam.

A fertility study of piperacillin/ tazobactam reported a decrease in litter size and an increase in fetuses with ossification delays and variations of ribs following i.p. administration. Fertility of the F1 generation and embryonic development of the F2 generation was not impaired. A teratogenicity study in rats, did not show teratogenic effects after i.v. administration. In the rat, effects on the embryonic development were observed at maternal toxic doses. Peri/postnatal development was impaired (reduced fetal weights, increase in pup mortality, increase in stillbirths) concurrently with maternal toxicity after i.p. administration in the rat.

6. Pharmaceutical Particulars

6.1 List Of Excipients

None.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Whenever Piperacillin / Tazobactam is used concurrently with another antibiotic (e.g. aminoglycosides), the drugs must be administered separately. The mixing of Piperacillin / Tazobactam with an aminoglycoside in vitro can result in substantial inactivation of the aminoglycoside.

Piperacillin / Tazobactam should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.

Piperacillin/Tazobactam should be administered through an infusion set separately from any other drugs unless compatibility is proven.

Due to chemical instability, Piperacillin / Tazobactam should not be used with solutions that contain sodium bicarbonate.

Lactated Ringer's (Hartmann´s) solution is not compatible with piperacillin/tazobactam.

Piperacillin / Tazobactam should not be added to blood products or albumin hydrolysates.

6.3 Shelf Life

Vial before opening: 2 years

Vial after first opening/after reconstitution:

After reconstitution (and dilution):

Reconstituted and/or diluted Piperacillin/Tazobactam should be used immediately.

From a microbiological point of view, the product should be used immediately.

Unused solution should be discarded.

6.4 Special Precautions For Storage

Un opened: Store in the original package in order to protect from light.

Store below 25°C.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Clear glass vials of 30 ml stoppered with grey colour bromo butyl rubber stopper and sealed with violet colour PP/Al flip off seal.

Pack sizes: 1 and 12 vials per carton.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Reconstitution Directions

Intravenous Injection:

Each vial of Piperacillin / tazobactam 2g/0.25g should be reconstituted with 10ml of one of the following diluents:

• Sterile Water for Injection

• 9 mg/ml (0.9%) Sodium Chloride for Injection

• Dextrose 50 mg/ml (5%) in water

• Dextrose 50 mg/ml (5%) in sodium chloride 9 mg/ml (0.9%) solution

Swirl until dissolved. Intravenous injection should be given over at least 3-5 minutes.

Intravenous Infusion:

Each vial of Piperacillin / Tazobactam 2g/0.25g should be reconstituted with 10ml of one of the above diluents:

The reconstituted solution should be further diluted to a total volume of 50 ml to 100 ml with one of the reconstitution diluents, or with dextran 60 mg/ml (6%) in sodium chloride 9 mg/ml (0.9%) solution. Intravenous infusion should be given over 20-30 minutes.

For single use only. Discard any unused solution.

The reconstitution/dilution is to be made under aseptic conditions. The reconstituted solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

Milpharm Limited

Ares, Odyssey Business Park

West End Road

South Ruislip HA4 6QD

United Kingdom

8. Marketing Authorisation Number(S)

PL 16363/0220

9. Date Of First Authorisation/Renewal Of The Authorisation

06/11/2009

10. Date Of Revision Of The Text

06/11/2009

POLLENSHIELD HAYFEVER (P)

1. Name Of The Medicinal Product

Cetirizine Hydrochloride 10mg Tablets

POLLENSHIELD HAYFEVER

2. Qualitative And Quantitative Composition

Each tablet contains 10mg Cetirizine hydrochloride.

For a full list of excipients, see 6.1

3. Pharmaceutical Form

Film-coated tablet.

Film-coated, white or almost white convex, elliptical, tablets. 5.7 x 11.4mm. The letter “C” on one side and the letters “J” and “E” on either side of a central division line on the reverse.

4. Clinical Particulars

4.1 Therapeutic Indications

In adults and paediatric patients 6 year and above:

- Cetirizine is indicated for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis.

- Cetirizine is indicated for the relief of symptoms of chronic idiopathic urticaria.

4.2 Posology And Method Of Administration

Children aged from 6 to 12 years: 5mg twice daily (a half tablet twice daily).

Adults and adolescents over 12 years of age: 10mg once daily (1 tablet).

The tablets need to be swallowed with a glass of liquid.

Elderly subjects: data do not suggest that the dose needs to be reduced in elderly subjects provided that the renal function is normal.

Patients with moderate to severe renal impairment: there are no data to document the efficacy/safety ratio in patients with renal impairement. Since cetirizine is mainly excreted via renal route (see section 5.2), in cases no alternative treatment can be used, the dosing intervals must be individualized according to renal function. Refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr (ml/min) may be estimated from serum creatinine (mg/dl) determination using the following formula:

Dosing adjustments for adult patients with impaired renal function

Group	Creatinine clearance (ml/min)	Dosage and frequency
Normal			10mg once daily
Mild		50 – 79	10mg once daily
Moderate		30 – 49	5mg once daily
Severe		<30	5mg once every 2 days
End-stage renal disease	<10	Contra-indicated
Patients undergoing dialysis

In paediatric patients suffering from renal impairment, the dose will have to be adjusted on an individual basis taking into account the renal clearance of the patient, his age and his body weight.

Patients with hepatic impairment: no dose adjustment is needed in patients with solely hepatic impairment.

Patients with hepatic impairment and renal impairment: dose adjustment is recommended (see Patients with moderate to severe renal impairment above).

Method of Administration

For oral use.

4.3 Contraindications

Hypersensitivity to the active substance, to any of the excipients, to hydroxyzine or to any piperazine derivatives.

Patients with severe renal impairment at less than 10ml/min creatinine clearance.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose- galactose malabsorption should not take cetirizine film-coated tablet.

4.4 Special Warnings And Precautions For Use

At therapeutic doses, no clinically significant interactions have been demonstrated with alcohol (for a blood alcohol level of 0.5g/L). Nevertheless, precaution is recommended if alcohol is taken concomitantly.

Caution in epileptic patients and patients at risk of convulsions is recommended.

The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation.

Allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Due to the pharmacokinetic, pharmacodynamic and tolerance profile of cetirizine, no interactions are expected with this antihistamine. Actually, neither pharmacodynamic nor significant pharmacokinetic interaction was reported in drug-drug interactions studies performed, notably with pseudoephedrine or theophylline (400mg/day).

The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased.

4.6 Pregnancy And Lactation

Pregnancy

For cetirizine very rare clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.

Lactation

Cetirizine is excreted in human milk at concentrations representing 0.25 to 0.90 those measured in plasma, depending on sampling time after administration. Therefore, caution should be exercised when prescribing cetirizine to lactating women.

4.7 Effects On Ability To Drive And Use Machines

Objective measurements of driving ability, sleep latency and assembly line performance have not demonstrated any clinically relevant effects at the recommended dose of 10mg. Patients intending to drive, engaging in potentially hazardous activities or operating machinery should not exceed the recommended dose and should take their response to the medicinal product into account. In these sensitive patients, concurrent use with alcohol or other CNS depressants may cause additional reductions in alertness and impairment of performance.

4.8 Undesirable Effects

Clinical studies have shown that cetirizine at the recommended dosage has minor undesirable effects on the CNS, including somnolence, fatigue, dizziness and headache. In some cases, paradoxical CNS stimulation has been reported.

Although cetirizine is a selective antagonist of peripheral H₁-receptors and is relatively free of anticholinergic activity, isolated cases of micturition difficulty, eye accommodation disorders and dry mouth have been reported.

Instances of abnormal hepatic function with elevated hepatic enzymes accompanied by elevated bilirubin have been reported. Mostly this resolves upon discontinuation of the treatment with cetirizine dihydrochloride.

Clinical trials

Double blind controlled clinical or pharmacoclinical trials comparing cetirizine to placebo or other antihistamines at the recommended dosage (10mg daily for cetirizine), of which quantified safety data are available, included more than 3200 subjects exposed to cetirizine. From this pooling, the following adverse events were reported for cetirizine 10mg in the placebo-controlled trials at rates of 1.0% or greater:

Adverse event	Cetirizine 10mg	Placebo
(WHO-ART)	(n= 3260)	(n = 3061)
Body as a whole – general disorders
Fatigue	1.63%	0.95%
Central and peripheral nervous system disorders
Dizziness	1.10%	0.98%
Headache	7.42%	8.07%
Gastro-intestinal system disorders
Abdominal pain	0.98%	1.08%
Dry mouth	2.09%	0.82%
Nausea	1.07%	1.14%
Psychiatric disorders
Somnolence	9.63%	5.00%
Respiratory system disorders
Pharyngitis	1.29%	1.34%

Although statistically more common than under placebo, somnolence was mild to moderate in the majority of cases. Objective tests as demonstrated by other studies have demonstrated that usual daily activities are unaffected at the recommended daily dose in healthy young volunteers.

Adverse drug reactions at rates of 1% or greater in children aged from 6 months to 12 years, included in placebo-controlled clinical or pharmacoclinical trials are:

Adverse drug reactions (WHO-ART)	Cetirizine (n=1656)	Placebo (n =1294)
Gastro-intestinal system disorders Diarrhoea	1.0%	0.6%
Psychiatric disorders Somnolence	1.8%	1. 4%
Respiratory system disorders Rhinitis	1.4%	1.1%
Body as a whole – general disorders Fatigue	1.0%	0.3%

Post-marketing experience

In addition to the adverse effects reported during clinical studies and listed above, isolated cases of the following adverse drug reactions have been reported in post-marketing experience.

Frequencies are defined as follows: Very common (

Blood and lymphatic disorders:

Very rare: thrombocytopenia

Immune system disorders:

Rare: hypersensitivity

Very rare: anaphylactic shock

Psychiatric disorders:

Uncommon: agitation

Rare: aggression, confusion, depression, hallucination, insomnia

Very rare: tic

Nervous system disorders:

Uncommon: paraesthesia

Rare: convulsions, movements disorders

Very rare: dysgeusia, syncope, tremor, dystonia, dyskinesia

Not known: amnesia, memory impairment

Eye disorders:

Very rare: accommodation disorder, blurred vision, oculogyration

Cardiac disorders:

Rare: tachycardia

Gastro-intestinal disorders:

Uncommon: diarrhoea

Hepatobiliary disorders:

Rare: hepatic function abnormal (increased transaminases, alkaline phosphatase, γ-GT and bilirubin)

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, rash

Rare: urticaria

Very rare: angioneurotic oedema, fixed drug eruption

Renal and urinary disorders:

Very rare: dysuria, enuresis

General disorders and administration site conditions:

Uncommon: asthenia, malaise

Rare: oedema

Investigations:

Rare: weight increased

4.9 Overdose

Symptoms

Symptoms observed after an overdose of cetirizine are mainly associated with CNS effects or with effects that could suggest an anticholinergic effect.

Adverse events reported after an intake of at least 5 times the recommended daily dose are: confusion, diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinary retention.

Management

There is no known specific antidote to cetirizine.

Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered following ingestion of a short occurrence.

Cetirizine is not effectively removed by dialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Piperazine derivatives, ATC code: R06A E07

Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral H₁receptors. In vitro receptor binding studies have shown no measurable affinity for other than H₁receptors.

In addition to its anti-H₁ effect, cetirizine was shown to display anti-allergic activities: at a dose of 10mg once or twice daily, it inhibits the late phase recruitment of eosinophils, in the skin and conjunctiva of atopic subjects submitted to allergen challenge.

Studies in healthy volunteers show that cetirizine, at doses of 5 and 10mg strongly inhibits the wheal and flare reactions induced by very high concentrations of histamine into the skin, but the correlation with efficacy is not established. In a 35-day study in children aged 5 to 12, no tolerance to the antihistaminic effect (suppression of wheal and flare) of cetirizine was found. When a treatment with cetirizine is stopped after repeated administration, the skin recovers its normal reactivity to histamine within 3 days.

In a six-week, placebo-controlled study of 186 patients with allergic rhinitis and concomitant mild to moderate asthma, cetirizine 10mg once daily improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering cetirizine to allergic patients with mild to moderate asthma.

In a placebo-controlled study, cetirizine given at the high daily dose of 60mg for seven days did not cause statistically significant prolongation of QT interval.

At the recommended dosage, cetirizine has demonstrated that it improves the quality of life of patients with perennial and seasonal allergic rhinitis.

5.2 Pharmacokinetic Properties

The steady - state peak plasma concentrations is approximately 300ng/ml and is achieved within 1.0 ± 0.5 h. No accumulation is observed for cetirizine following daily doses of 10mg for 10 days. The distribution of pharmacokinetic parameters such as peak plasma concentration (C_max) and area under curve (AUC), is unimodal in human volunteers.

The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased. The extent of bioavailability is similar when cetirizine is given as solutions, capsules or tablets.

The apparent volume of distribution is 0.50l/kg. Plasma protein binding of cetirizine is 93 ± 0.3%. Cetirizine does not modify the protein binding of warfarin.

Cetirizine does not undergo extensive first pass metabolism. About two third of the dose are excreted unchanged in urine. The terminal half-life is approximately 10 hours.

Cetirizine exhibits linear kinetics over the range of 5 to 60mg.

Special populations

Elderly: Following a single 10mg oral dose, half-life increased by about 50% and clearance decreased by 40% in 16 elderly subjects compared to the normal subjects. The decrease in cetirizine clearance in these elderly volunteers appeared to be related to their decreased renal function.

Children, infants and toddlers: The half-life of cetirizine was about 6 hours in children of 6-12 years and 5 hours in children 2-6 years. In infants and toddlers aged 6 to 24 months, it is reduced to 3.1 hours

Renally impaired patients: The pharmacokinetics of the drug were similar in patients with mild impairment (creatinine clearance higher than 40ml/min) and healthy volunteers. Patients with moderate renal impairment had a 3-fold increase in half-life and 70% decrease in clearance compared to healthy volunteers.

Patients on hemodialysis (creatinine clearance less than 7ml/min) given a single oral 10mg dose of cetirizine had a 3-fold increase in half-life and a 70% decrease in clearance compared to normals. Cetirizine was poorly cleared by haemodialysis. Dosing adjustment is necessary in patients with moderate or severe renal impairment (see section 4.2).

Hepatically impaired patients: Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20mg of cetirizine as a single dose had a 50% increase in half-life along with a 40% decrease in clearance compared to healthy subjects.

Dosing adjustment is only necessary in hepatically impaired patients if concomitant renal impairment is present.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

Microcrystalline cellulose (E460), lactose monohydrate, crospovidone, colloidal anhydrous silica, magnesium stearate.

Film coat:

Hypromellose (E464), macrogol stearate, microcrystalline cellulose (E460), propylene glycol, titanium dioxide (E171).

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Blister pack:

Do not store above 25°C.

Store in the original package

6.5 Nature And Contents Of Container

Blister pack

(i) 60µm PVC/45µm Al/25µm OPA

(ii) 20µm Al

HDPE tablet container with LDPE cap.

HDPE tablet container: 20, 28, 30, 56, 60, 100

Blister pack: 7, 20, 28, 30, 56, 60, 100

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Actavis UK Limited

(Trading style : Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

8. Marketing Authorisation Number(S)

PL 0142/0490

9. Date Of First Authorisation/Renewal Of The Authorisation

27.06.2001

Renewal - 05/04/2011

10. Date Of Revision Of The Text

05/04/2011

11 DOSIMETRY

(IF APPLICABLE)

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

(IF APPLICABLE)

Pantoprazole 40 mg gastro-resistant tablets (Actavis UK Ltd)

1. Name Of The Medicinal Product

Pantoprazole 40 mg gastro-resistant tablets

2. Qualitative And Quantitative Composition

Each gastro-resistant tablet contains 40 mg pantoprazole

(as pantoprazole sodium sesquihydrate 45.16 mg)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gastro-resistant tablet

Elliptical, biconvex, dark yellow gastro-resistant tablet

4. Clinical Particulars

4.1 Therapeutic Indications

Adults and adolescents 12 years of age and above

• Reflux oesophagitis.

Adults

• Eradication of Helicobacter pylori (H. pylori) in combination with appropriate antibiotic therapy in patients with H. pylori associated ulcers.

• Gastric and duodenal ulcer.

• Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions.

4.2 Posology And Method Of Administration

Tablets should not be chewed or crushed, and should be swallowed whole 1 hour before a meal with some water.

Recommended dose

Adults and adolescents 12 years of age and above

Reflux oesophagitis

One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Adults

Eradication of H. pylori in combination with two appropriate antibiotics in H. pylori positive patients with gastric and duodenal ulcers, eradication of the germ by a combination therapy should be achieved. Considerations should be given to official local guidance (e.g. national recommendations) regarding bacterial resistance and the appropriate use and prescription of antibacterial agents. Depending upon the resistance pattern, the following combinations can be recommended for the eradication of H. pylori:

a) twice daily one tablet Pantoprazole tablets

+ twice daily 1000 mg amoxicillin

+ twice daily 500 mg clarithromycin

b) twice daily one tablet Pantoprazole tablets

+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)

+ twice daily 250 - 500 mg clarithromycin

c) twice daily one tablet Pantoprazole tablets

+ twice daily 1000 mg amoxicillin

+ twice daily 400 - 500 mg metronidazole (or 500 mg tinidazole)

In combination therapy for eradication of H. pylori infection, the second Pantoprazole tablets tablet should be taken 1 hour before the evening meal. The combination therapy is implemented for 7 days in general and can be prolonged for a further 7 days to a total duration of up to two weeks. If, to ensure healing of the ulcers, further treatment with pantoprazole is indicated, the dose recommendations for duodenal and gastric ulcers should be considered.

If combination therapy is not an option, e.g. if the patient has tested negative for H. pylori, the following dose guidelines apply for Pantoprazole tablets monotherapy:

Treatment of gastric ulcer

One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A 4-week period is usually required for the treatment of gastric ulcers. If this is not sufficient, healing will usually be achieved within a further 4 weeks.

Treatment of duodenal ulcer

One tablet of Pantoprazole tablets per day. In individual cases the dose may be doubled (increase to 2 tablets Pantoprazole tablets daily) especially when there has been no response to other treatment. A duodenal ulcer generally heals within 2 weeks. If a 2-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further 2 weeks.

Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions

For the long-term management of Zollinger-Ellison-Syndrome and other pathological hypersecretory conditions patients should start their treatment with a daily dose of 80 mg (2 tablets of Pantoprazole tablets 40 mg). Thereafter, the dose can be titrated up or down as needed using measurements of gastric acid secretion to guide. With doses above 80 mg daily, the dose should be divided and given twice daily. A temporary increase of the dose above 160 mg pantoprazole is possible but should not be applied longer than required for adequate acid control.

Treatment duration in Zollinger-Ellison syndrome and other pathological hypersecretory conditions is not limited and should be adapted according to clinical needs.

Special populations

Children below 12 years of age

Pantoprazole tablets is not recommended for use in children below 12 years of age due to limited data on safety and efficacy in this age group.

Hepatic Impairment

A daily dose of 20 mg pantoprazole (1 tablet of 20 mg pantoprazole) should not be exceeded in patients with severe liver impairment. Pantoprazole tablets must not be used in combination treatment for eradication of H. pylori in patients with moderate to severe hepatic dysfunction since currently no data are available on the efficacy and safety of Pantoprazole tablets in combination treatment of these patients (see section 4.4).

Renal Impairment

No dose adjustment is necessary in patients with impaired renal function. Pantoprazole tablets must not be used in combination treatment for eradication of H. pylori in patients with impaired renal function since currently no data are available on the efficacy and safety of Pantoprazole tablets in combination treatment for these patients.

Elderly

No dose adjustment is necessary in elderly patients.

4.3 Contraindications

Hypersensitivity to the active substance, substituted benzimidazoles or to any of the excipients

4.4 Special Warnings And Precautions For Use

Hepatic Impairment

In patients with severe liver impairment, particularly those on long-term use, liver enzymes should be monitored regularly during treatment with pantoprazole. In the case of a rise in liver enzymes, pantoprazole 40mg gastro-resistant tablets should be discontinued.

Combination therapy

In the case of combination therapy, the summaries of product characteristics of the respective medicinal products should be observed.

In presence of alarm symptoms

In the presence of any alarm symptom (e. g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded, as treatment with pantoprazole may alleviate symptoms and delay diagnosis.

Further investigation is to be considered if symptoms persist despite adequate treatment.

Co-administration with atazanavir

Co-administration of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If the combination of atazanavir with a proton pump inhibitor is judged unavoidable, close clinical monitoring (e.g virus load) is recommended in combination with an increase in the dose of atazanavir to 400mg with 100mg of ritonavir. A pantoprazole dose of 20mg per day should not be exceeded.

Influence on vitamin B12 absorption

In patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, pantoprazole, as all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy or if respective clinical symptoms are observed.

Long term treatment

In long-term treatment, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

Gastrointestinal infections caused by bacteria

Pantoprazole, like all proton pump inhibitors (PPIs), might be expected to increase the counts of bacteria normally present in the upper gastrointestinal tract. Treatment with Pantoprazole may lead to a slightly increased risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter.

To date, there has been no experience with treatment in children.

Note:

Prior to treatment of gastric ulcer, the possibility of malignancy should be excluded as treatment with pantoprazole 40mg gastro-resistant tablets may alleviate the symptoms of malignant ulcers and can thus delay diagnosis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effect of pantoprazole on the absorption of other medicinal products

Because of profound and long lasting inhibition of gastric acid secretion, pantoprazole may reduce the absorption of drugs with a gastric pH dependent bioavailability, e.g some azole antifungals as ketoconazole, itraconazole, posaconazole and other medicine as erlotinib.

HIV medications (atazanavir)

Co-administration of atazanavir and other HIV medications whose absorption is pH-dependent with proton-pump inhibitors might result in a substantial reduction in the bioavailability of these HIV medications and might impact the efficacy of these medicines. Therefore, the co-administration of proton pump inhibitors with atazanavir is not recommended (see section 4.4).

Coumarin anticoagulants (phenprocoumon or warfarin)

Although no interaction during concomitant administration of phenprocoumon or warfarin has been observed in clinical pharmacokinetic studies, a few isolated cases of changes in INR have been reported during concomitant treatment in the post-marketing period. Therefore, in patients treated with coumarin anticoagulants, monitoring of prothrombin time/INR is recommended after initiation, termination or during irregular use of pantoprazole.

Other interactions studies

Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways include oxidation by CYP3A4. Interaction studies with drugs also metabolized with these pathways, like carbamazepine, diazepam, glibenclamide, nifedipine, and an oral contraceptive containing levonorgestrel and ethinyl oestradiol did not reveal clinically significant interactions.

Results from a range of interaction studies demonstrate that pantoprazole does not effect the metabolism of active substances metabolised by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol) or does not interfere with p-glycoprotein related absorption of digoxin.

There were no interactions with concomitantly administered antacids.

Interaction studies have also been performed administering pantoprazole concomitantly with the respective antibiotics (clarithromycin, metronidazole, amoxicillin) No clinically relevant interactions were found.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Pantoprazole should not be used during pregnancy unless clearly necessary.

Lactation

Animal studies have shown excretion of pantoprazole in breast milk. Excretion into human milk has been reported. Therefore a decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with pantoprazole should be made taking into account the benefit of breastfeeding to the child and the benefit of pantoprazole therapy to women.

4.7 Effects On Ability To Drive And Use Machines

Adverse drug reactions such as dizziness and visual disturbances may occur (see section 4.8). If affected, patients should not drive or operate machines.

4.8 Undesirable Effects

Approximately 5 % of patients can be expected to experience adverse drug reactions (ADRs). The most commonly reported ADRs are diarrhoea and headache, both occurring in approximately 1 % of patients.

The table below lists adverse reactions reported with pantoprazole, ranked under the following frequency classification:

very common (

common (

uncommon (

rare (

very rare (<1/10,000),

not known (cannot be estimated from the available data).

For all adverse reactions reported from post-marketing experience, it is not possible to apply any Adverse

Reaction frequency and therefore they are mentioned with a “not known” frequency.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions with pantoprazole in clinical trials and post-marketing experience

Frequency Organ system	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system			Thrombocytopenia Leukopenia;
Immune system disorders		Hypersensitivity (including anaphylactic reactions and anaphylactic shock)
Metabolism and nutritional disorders		Hyperlipidaemias and lipid increases (triglycerides, cholesterol); Weight changes		Hyponatraemia
Psychiatric disorders	Sleep disorders	Depression (and all aggravations)	Disorientation (and all aggravations)	Hallucination; Confusion (especially in pre-disposed patients, as well as the aggravation of these symptoms in case of pre-existence)
Nervous system disorders	Headache; Dizziness
Eye disorders		Disturbances in vison/ blurred vision
Gastrointestinal Disorders	Diarrhoea; Nausea /vomiting; Abdominal distension and bloating; Constipation; Dry mouth; Abdominal pain and discomfort Flatulence
Hepatobiliary disorders	Liver enzymes increased (transaminases, γ-GT)	Bilirubin increased		Hepatocellular injury; Jaundice; Hepatocellular failure
Skin and subcutaneous tissue disorders	Rash / exanthema / eruption; Pruritus	Urticaria; Angioedema		Stevens-Johnson syndrome; Lyell syndrome; Erythema multiforme; Photosensitivity
Musculoskeletal, connective tissue disorders		Arthralgia; Myalgia
Renal and urinary disorders				Interstitial nephritis
Reproductive system and breast disorders		Gynaecomastia
General disorders and administration site conditions	Asthenia, fatigue and malaise	Body temperature increased; Oedema peripheral

4.9 Overdose

There are no known symptoms of overdose in man.

Systemic exposure with up to 240mg administered intravenously over 2 minutes were well tolerated.

As pantoprazole is extensively protein bound, it is not readily dialysable.

In the case of overdose with clinical signs of intoxication, apart from symptomatic and supportive treatment, no specific therapeutic recommendations can be made.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: proton pump inhibitors, ATC code: A02BC02

Mechanism of action

Pantoprazole is a substituted benzimidazole which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells.

Pantoprazole is converted to its active form in the acidic environment in the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the cell receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the product is given orally or intravenously.

The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during longterm treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments (see section 5.3) have not been observed in humans.

An influence of a long term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies.

5.2 Pharmacokinetic Properties

General pharmacokinetics

Absorption

Pantoprazole is rapidly absorbed and the maximal plasma concentration is achieved even after one single 40mg oral dose. On average at about 2.5 h p.a. the maximum serum concentrations of about 2 - 3 μg/ml are achieved, and these values remain constant after multiple administration.

Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80mg, the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.

The absolute bioavailability from the tablet was found to be about 77 %. Concomitant intake of food had no influence on AUC, maximum serum concentration and thus bioavailability. Only the variability of the lag-time will be increased by concomitant food intake.

Distribution

Pantoprazole's serum protein binding is about 98 %. Volume of distribution is about 0.15 l/kg

Elimination

The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathway include oxidation by CYP3A4. Terminal half-life is about 1 hour and clearance is about 0.1 l/h/kg. There were a few cases of subjects with delayed elimination. Because of the specific binding of pantoprazole to the proton pumps of the parietal cell the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion).

Renal elimination represents the major route of excretion (about 80 %) for the metabolites of pantoprazole, the rest is excreted with the faeces. The main metabolite in both the serum and urine is desmethylpantoprazole which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of pantoprazole.

Characteristics in patients/special groups of subjects

Approximately 3 % of the European population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals the metabolism of pantoprazole is probably mainly catalysed by CYP3A4. After a single-dose administration of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60 %. These findings have no implications for the posology of pantoprazole.

No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (including dialysis patients). As with healthy subjects, pantoprazole's half-life is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately delayed halflife (2 - 3 h), excretion is still rapid and thus accumulation does not occur.

Although for patients with liver cirrhosis (classes A and B according to Child) the half-life values increased to between 7 and 9 h and the AUC values increased by a factor of 5 - 7, the maximum serum concentration only increased slightly by a factor of 1.5 compared with healthy subjects.

A slight increase in AUC and C_max in elderly volunteers compared with younger counterparts is also not clinically relevant.

Children

Following administration of single oral doses of 20 or 40 mg pantoprazole to children aged 5 - 16 years AUC and C_max were in the range of corresponding values in adults.

Following administration of single i.v. doses of 0.8 or 1.6 mg/kg pantoprazole to children aged 2 - 16 years there was no significant association between pantoprazole clearance and age or weight. AUC and volume of distribution were in accordance with data from adults.

5.3 Preclinical Safety Data

Preclinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.

In the two-year carcinogenicity studies in rats neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the forestomach of rats. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-dose treatment. In the two-year rodent studies an increased number of liver tumors was observed in rats and in female mice and was interpreted as being due to pantoprazole's high metabolic rate in the liver.

A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg). The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects on the thyroid glands are expected.

In animal reproduction studies, signs of slight fetotoxicity were observed at doses above 5 mg/kg.

Investigations revealed no evidence of impaired fertility or teratogenic effects.

Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentration of pantoprazole in the foetus is increased shortly before birth.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol

Sodium carbonate anhydrous

Sodium starch glycolate, Type A

Methacrylic acid copolymer

Calcium stearate

Opadry white OY-D-7233 (hypromellose, titanium dioxide, talc, macrogol, sodium lauryl sulphate)

Kollicoat MAE 30 DP yellow (methacrylic acid-ethyl acrylate copolymer dispersion 30%, propylene glycol, yellow iron oxide, titanium dioxide, talc)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Pantoprazole 40mg gastro-resistant tablets are provided in aluminium/aluminium blister packs of 2, 7, 14, 15, 28, 30, 50, 56, 60, 84, 90, 100, 112, 140, 280, 500, or 700 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements

7. Marketing Authorisation Holder

Actavis Group PTC ehf

Reykjavikurvegur 76-78

220 Hafnarfjordur

Iceland

8. Marketing Authorisation Number(S)

PL 30306/0299

9. Date Of First Authorisation/Renewal Of The Authorisation

29/04/2010

10. Date Of Revision Of The Text

20.10.2011