Retarpen is indicated in adults, adolescents, children and neonates for the treatment  and  prophylaxis of the following infections caused by pathogens sensitive to penicillin (see section 5.1):

For the treatment of:

-         erysipelas

-                 syphilis: early syphilis (primary and secondary)

-                 latent syphilis (except for neurosyphilis and presence of pathological CSF findings)

-                 yaws

-                 pinta

For the prophylaxis of:

-                 rheumatic fever (chorea, rheumatic carditis)

-                 poststreptococcal glomerulonephritis

-                 erysipelas

When using Retarpen, consideration should be given to the general guidelines on the appropriate  use of antibacterial agents.

The dosing recommendations depend on the severity and the type of infection, the age and the hepato- renal function of patients. International guidelines should be considered in addition to national or   local guidance for some specific indications (eg syphilis, prophylaxis of rheumatic fever).

Dosage and duration of treatment

General therapy:

Adults and adolescents:             1.2 mio IU once weekly Children > 30 kg body weight: 1.2 mio IU once weekly Children < 30 kg body weight: 600,000 IU once weekly Duration of treatment:                                                single dose

(In streptococcal diseases, a 10-day minimum course of treatment should be observed to avoid secondary  diseases.  This  is  generally ensured  with  a  single  injection of {Retarpen} 600,000    IU,

{Retarpen} 1.2 mio IU or {Retarpen} 2.4 mio IU.)

Treatment of syphilis:

•                Primary and secondary stage

Adults and adolescents:             1 x 2.4 mio IU

Children:                                  50,000 IU/kg body weight, however not more than 2.4 mio IU

(If clinical symptoms recur or laboratory findings remain strongly positive, treatment should be repeated.)

Duration of treatment:               single dose

•                Late-stage syphilis (latent seropositive syphilis)

Adults and adolescents:             2.4 mio IU once weekly

Children:                                  50,000 IU/kg body weight, however not more than 2.4 mio IU

Duration of treatment:               3 weeks

•                Treatment of congenital syphilis: without neurological involvement

Neonates and infants:                1 x 50,000 IU/kg body weight Duration of treatment:                                           single dose

Treatment of yaws, pinta:

Adults and adolescents:                              1 x 1.2 mio IU Children > 30 kg body weight: 1 x 1.2 mio IU Children < 30 kg body weight: 1 x 600,000 IU Duration of treatment:                                 single dose

Prophylaxis of rheumatic fever, poststreptococcal glomerulonephritis and erysipelas:

Adults and adolescents:             1 x 1.2 mio IU every 3-4 weeks Children > 30 kg body weight: 1 x 1.2 mio IU every 3-4 weeks Children < 30 kg body weight: 1 x 600,000 IU every 3-4 weeks Duration of treatment:

a)  without cardiac involvement: at least 5 years, or up to 21 years of age

b)  transient cardiac involvement: at least 10 years, or up to 21 years of age

c)  persistent cardiac involvement: at least 10 years or up to 40 years of age; life-long prophylaxis is sometimes necessary.

Special patient groups

Patients with impaired renal function

Haemodialysis patients

Benzathin-Benzylpenicillin can be removed by hemodialysis. There are no data available on the influence of dialysis on the plasma levels of benzyl penicillin. The decision to treat patients on  dialysis with {Retarpen} needs therefore to be taken on a case by case basis.

Patients with impaired hepatic function

In very severe cases of impaired hepatic and renal function, there may be a delay in the degradation and excretion of penicillins.

Method of administration

The preparation is strictly for intramuscular injection (see section 4.4).

The injection must not be administered into tissue with reduced perfusion (see section 4.4).

{Retarpen} should be administered by deep intramuscular injection into the upper, outer quadrant of the gluteus maximus or Hochstetter's ventrogluteal field, with the needle pointing towards the iliac crest or according to von Hochstetter's method. The puncture should be as vertical to the skin surface as possible and the injection as far away from major vessels as possible. In all events, aspiration must be performed prior to the injection. If aspiration of blood or pain occurs during the injection, it must  be discontinued.

In children, the mid-lateral thigh muscles (quadriceps femoris) are recommended as an injection site. The deltoid muscle is only suitable if it is well formed; in this case, attention must be paid to the  radial nerve.

In infants and young children, the peripheral area of the upper outer quadrant of the gluteal region should be used as the area for injection only in exceptional cases (e.g. widespread burns), in order to avoid sciatic nerve lesions.

For depot preparations, a total volume of 5 ml per injection site is stated as the tolerance limit. Thus, no more than 5 ml of the ready-to-inject suspension should be administered at any one time into one site.

The injection should be given as slowly as possible and only with the application of low pressure. “Rubbing” after the injection should be avoided.

Severe local reactions may occur during intramuscular administration, especially in young children. If possible, taking notably into account the therapeutic indications and schedule regimens and weighing the benefit-risk ratio, alternative treatments such as intravenous therapy with a suitable penicillin product should be considered (see also section 4.4).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Retarpen should not be used in tissues with reduced perfusion.

Before initiating therapy with Retarpen, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8).

Serious and occasionally fatal hypersentivity reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, Retarpen must be  discontinued and appropriate therapy instituted.

Prior to treatment, a hypersensitivity test should be performed if possible. The patient should be made aware of the possible occurrence of allergic symptoms and of the need to report them.

Caution should be exercised in patients with the following conditions:

•                allergic diathesis or bronchial asthma (there is an increased risk of a hypersensitivity  reaction):

•                in renal insufficiency (for dose adjustment, see section 4.2);

•                in impaired hepatic function (see section 4.2);

Based on a general principle, in particular in some exposed patients, a medical observation should if possible be ensured for at last half an hour after the administration of this antibiotic, as severe immediate allergic reactions may occur even after the first administration.

When treating syphilis, a Jarisch-Herxheimer reaction may occur as a result of the bactericidal action of penicillin on pathogens. 2 to 12 hours after administration headaches, fever, sweating, shivering, myalgia, arthralgia, nausea, tachycardia, increased blood pressure followed by hypotension  may occur. These symptoms resolve after 10 to 12 hours. Patients should be informed that this is a usual, transient sequela of antibiotic therapy. Appropriate therapy should be instituted to suppress or  attenuate a Jarisch-Herxheimer reaction (see section 4.8).

In long-term treatment (more than 5 days), blood count monitoring and renal function tests are recommended.

Vigilance is required for overgrowth of resistant germs. At the onset of secondary infections, appropriate measures should be taken.

In the event of severe and persistent diarrhoea, antibiotic-associated pseudomembranous colitis (bloody/mucoid, watery diarrhoea, dull, diffuse-to-colicky abdominal pain, fever, occasionally tenesmus) should be considered, which can be life-threatening. In these cases, {Retarpen} should therefore be discontinued immediately and therapy instituted based on pathogen detection results. Antiperistaltic agents are contraindicated.

If neurological involvement cannot be excluded in patients with congenital syphilis, forms of  penicillin that reach a higher level in cerebrospinal fluid should be used.

In diseases such as severe pneumonia, empyema, sepsis, meningitis or peritonitis, which require  higher serum penicillin levels, alternative treatment such as the water-soluble alkali salt of benzyl penicillin should be considered.

Notes on administering Retarpen

Painful induration may occur in the event of accidental subcutaneous administration. Ice packs help in such cases.

In the event of inadvertent intravascular injection, Hoigné's syndrome may occur (symptoms of shock with mortal fear, confusion, hallucinations, possibly cyanosis, tachycardia and motor disorders, although no circulatory collapse), caused by microemboli of the suspension. The symptoms regress within an hour. If progression is severe, parenteral administration of sedatives is indicated.

In the event of inadvertent intra-arterial injection, particularly in children, serious complications may occur, such as vascular occlusion, thrombosis and gangrene. Initial signs are pale patches in the skin

area of the gluteal region. As a result of high injection pressure, retrograde entry of the injected liquid into the common iliac artery, aorta or spinal arteries may occur.

Repeated injections into a limited area of the muscle tissue, which are associated with long term therapy with depot-penicillins (e.g. in the treatment of syphilis) may induce tissue damage and increased local vascularization. Subsequent injections increase the possibility of penetration of injection substance into the blood, either by direct injection into a blood vessel or caused by the injection pressure itself, or by “rubbing” of the depot. During long term therapy it is therefore recommended to administer each injection on large distance from the precedent injection.

Decreased elimination of povidone should be considered in case of impairment of renal function. Due to the amount of povidone, it cannot be excluded that frequent or long term administration can lead in very rare cases to an accumulation of povidone in the reticulo-endothelial system (RES), or to a local deposition and formation of granulomas which may be confused with tumors.

Effect on diagnostic laboratory procedures:

-          A positive direct Coombs’ test often develops (≥ 1% to < 10%) in patients receiving 10 million  IU (equivalent to 6 g) benzylpenicillin or more per day. After discontinuation of the penicillin,  the direct antiglobulin test may still remain positive for 6 to 8 weeks (see section 4.8).

-          Determination of urinary protein using precipitation techniques (sulphosalicylic acid, trichloroacetic acid), the Folin-Ciocalteu-Lowry method or the biuret method may lead to false- positive results. Urinary protein should therefore be determined by other methods.

-          Urinary amino acid determination using the ninhydrin method may likewise lead to false-positive results.

-          Penicillins bind to albumin. In electrophoresis methods to determine albumin, pseudobisalbuminaemia may therefore be simulated.

-          During therapy with Retarpen, non-enzymatic urinary glucose detection and urobilinogen detection may prove false-positive.

-          When determining 17-ketosteroids (using the Zimmermann reaction) in the urine, increased values may occur during therapy with Retarpen.

Retarpen 600,000/1.2/2.4 MIU  contains phospholipids from the soja bean, caution is warranted on the risk of allergic reactions.

Retarpen 600,000 IU/1.2 MIU contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Retarpen 2.4 MIU powder and solvent for suspension for injection contains 40.1 mg sodium per dose, equivalent to 2.0% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Concomitant administration of benzathine benzylpenicillin is not recommended with:

Based on the general principle not to combine bactericidal and bacteriostatic antibiotics, Retarpen should not be combined with bacteriostatic antibiotics.

Caution should be exercised when co-administering the following:

Probenecid: the administration of probenecid leads to inhibition of the tubular secretion of benzylpenicillin, resulting in an increase in the serum concentration and prolongation of the elimination half-life. Furthermore probenicid inhibits the penicillin transport from the cerebrospinal fluid, so that the concomitant administration of probenecid reduces the penetration of benzyl  penicillin into brain tissue even further.

Methotrexate: when taken at the same time as benzathine benzylpenicillin, the excretion of methotrexate is reduced. This can lead to increased methotrexate toxicity. The combination with methotrexate is not recommended.

Anticoagulants: Concomitant use with oral anticoagulants may increase the anti-vitamin K effect and the risk of bleeding. It is recommended that the International Normalised Ratio (INR) is monitored frequently and the posology of the anti-vitamin K drug adjusted accordingly, both during and after treatment with Retarpen.

Pregnancy

Benzathine benzylpenicillin crosses the placenta. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Retarpen can be used during pregnancy when appropriately indicated and with due consideration of the benefits and risks.

Breast-feeding

Benzathine benzylpenicillin is excreted in human milk in small amounts. The concentration in maternal milk may reach 2 to 15% of the mother’s serum concentrations.

Although no undesirable effects in infants fed on breast milk have been reported to date,  consideration must nevertheless be given to the possibility of sensitisation or interference with the intestinal flora. Breast-feeding should be stopped in the case of occurrence of diarrhoea, candidosis or rash in the child.

In infants also being fed on baby food, mothers should express and discard breast milk during benzathine benzylpenicillin treatment. Breast-feeding can be resumed upon cessation of treatment 24 hours later.

Fertility

No fertility studies have been conducted in humans. Reproductive studies on mice, rats and rabbits have not revealed any negative effects on fertility. No long-term fertility studies on laboratory animals are available.

Due to the occurrence of possible serious undesirable effects (e.g. anaphylactic shock with collapse  and anaphylactoid reactions, see also section 4.8), Retarpen can have a major influence on the  ability to drive and use machines.

The undesirable effects are arranged according to body system and their frequency is categorised as follows:

Very common:              ≥ 1/10

Common:                     ≥ 1/100, < 1/10

Uncommon:                  ≥ 1/1,000, < 1/100

Rare:                            ≥ 1/10,000, < 1/1,000

Very rare                      < 1/10,000

Not known                    (cannot be estimated from the available data)

Infections and infestations

Common:          candidiasis

Blood and lymphatic system disorders

Very rare:          haemolytic anaemia, leukopenia, thrombocytopenia, agranulocytosis.

Immune system disorders

Rare:               allergic reactions: urticaria, angioedema, erythema multiforme, exfoliative dermatitis, fever, arthralgia, anaphylactic shock with collapse and anaphylactoid reactions (asthma, purpura, gastrointestinal symptoms).

Not known:       serum sickness. When treating syphilis, a Jarisch-Herxheimer reaction may occur as a result    of bacteriolysis, characterised by fever, chills, general and focal symptoms. In

patients with dermatomycosis, para-allergic reactions may occur, as common antigenicity may exist between penicillins and dermatophyte metabolites.

Gastrointestinal disorders

Common:          diarrhoea, nausea

Uncommon:      stomatitis and glossitis, vomiting

Not known:       pseudomembranous colitis  (see section 4.4).

Hepatobiliary disorders

Not known:       hepatitis, cholestasis

Renal and urinary disorders

Rare:                nephropathy, interstitial nephritis

General disorders and administration site conditions

Unknown:         pain at the injection site, injection site infiltrates Hoigné- and Nicolau Syndrome

Investigations

Common:

•                positive direct Coombs’ test.

•                false-positive urinary protein determination when precipitation techniques are used (Folin- Ciocalteu-Lowry method, biuret method).

•                false-positive urinary amino acid determination (ninhydrin method).

•                simulation of pseudobisalbuminaemia when using electrophoresis methods to determine albumin.

•                false-positive non-enzymatic urinary glucose detection and urobilinogen detection.

•                increased levels when determining 17-ketosteroids in urine (when the Zimmermann reaction   is used) (see section 4.4).

In infants, local reactions are possible.

It cannot be excluded that, in very rare cases and due to the povidone content, povidone may accumulate in the reticuloendothelial system (RES) or local deposits and foreign body granuloma may occur, which may be confused with tumors.

At extremely high doses, penicillins can induce neuromuscular excitability or epileptiform seizures. If overdose is suspected, clinical monitoring and  symptomatic  measures  are  indicated.  Benzylpenicillin can be haemodialysed.

Pharmacotherapeutic group

Antibacterials for systemic use, beta-lactamase sensitive penicillins. ATC code: J01CE08

Mode of action

For benzathine benzylpenicillin, the mechanism of action is based on an inhibition of bacterial cell wall synthesis (during the growth phase) through a blockade of the penicillin-binding proteins (PBPs), such as transpeptidases. This results in a bactericidal action.

Relationship between pharmacokinetics and pharmacodynamics

Efficacy largely depends on the length of time that the active substance level remains above the MIC of the pathogen.

Resistance mechanisms

Resistance to benzathine benzylpenicillin can be due to the following mechanisms:

-                 Inactivation by beta-lactamases: benzathine benzylpenicillin is not beta-lactamase-resistant  and therefore has no effect against beta-lactamase-producing bacteria (e.g. staphylococci or gonococci).

-                 Reduced affinity of PBPs for benzathine benzylpenicillin: the acquired resistance in pneumococci and a few other streptococci to benzathine benzylpenicillin is due to modifications of existing PBPs as a result of mutation. However, the formation of an additional PBP with reduced affinity for benzathine benzylpenicillin is responsible for resistance in methicillin (oxacillin)-resistant staphylococci.

-                 In Gram-negative bacteria, inadequate penetration of benzathine benzylpenicillin through the outer cell wall can lead to insufficient PBP inhibition.

-                 Benzathine benzylpenicillin can be actively transported from the cell by efflux pumps.

Benzathine benzylpenicillin is partially or completely cross-resistant to other penicillins and cephalosporins.

Breakpoints

Testing of benzylpenicillin is performed using the standard dilution series. Results are evaluated on  the basis of breakpoints for benzylpenicillin. The following minimum inhibitory concentrations have been established for susceptible and resistant germs:

EUCAST (European Committee on Antimicrobial Susceptibility Testing) breakpoints

*Based mainly on serum pharmacokinetics

# infections other than meningitis Prevalence of acquired resistance

The prevalence of acquired resistance in individual species may vary geographically and over time. Thus, local information on the resistance situation is required, particularly for the adequate treatment of severe infections. If, based on the local resistance situation, the efficacy of benzylpenicillin is questionable, expert therapeutic advice should be obtained. Particularly in cases of serious infection   or unsuccessful therapy, a microbiological diagnosis should be sought, with detection of the pathogen and its susceptibility to benzylpenicillin.

° Information derived from published literature, clinical experience and therapeutic guidelines.

^ Collective name for a heterogeneous group of streptococci species. The resistance rate can vary depending on the streptococci species present.

Pharmacokinetic data issued from the originator Retarpen dossier are old and information derived from them are limited. However published literature about benzathine benzylpenicillin, clinical experience and therapeutic guidelines can be taken into account.

Absorption

Following intramuscular administration of Retarpen, the absorption of benzylpenicillin is very slow. Retarpen is the longest-acting depot penicillin. For many indications, 1-2 injections per month are sufficient. Consequently, the frequency of injections and the resultant local trauma are reduced. Peak plasma levels are reached 24 hours (children) or 48 hours (adults) post-injection.

Distribution

About 55% of the administered dose is plasma protein-bound. When high-dose penicillin therapy is administered, therapeutically effective concentrations are reached even in poorly accessible tissues, such as heart valves, bone, as well as in the cerebrospinal fluid or in empyema, etc. Benzylpenicillin crosses the placenta. 10-30% of maternal plasma concentrations are found in the foetal circulation. High concentrations are also reached in the amniotic fluid. In contrast, transfer into milk is low. The volume of distribution is around 0.3-0.4 l/kg and about 0.75 l/kg in children. Plasma protein binding is approximately 55%.

Biotransformation and elimination

Elimination largely takes place (50 - 80%) as unchanged substance via the kidneys (85 - 95%) and, to  a lesser extent, in active form with the bile (about 5%).

The plasma half-life in adults with healthy kidneys is approximately 30 min.

Kinetics in special patient groups

·                Preterm and newborn infants: due to the immaturity of kidneys and liver at this age, the serum half-life is up to three hours (and more). The dosing interval must therefore be no shorter than 8 - 12 hours (depending on the degree of maturity).

·                Elderly patients: elimination processes may also be delayed with advanced age. The dosage should therefore be adjusted to individual renal function.

Reproductive studies in mice, rats and rabbits revealed no negative effects on fertility or on the foetuses. No long-term studies on laboratory animals are available with regard to carcinogenicity, mutagenicity and fertility.

Retarpen 600,000 IU - Powder and solvent for suspension for injection}: Povidone

Simethicone Sodium citrate Mannitol (E421).

1 vial of solvent contains: 5 ml water for injections Contains phospholipids from the soya beans

Retarpen 1.2 MIU - Powder and solvent for suspension for injection:

Povidone

Simethicone Sodium citrate Mannitol (E421).

1 vial of solvent contains: 5 ml water for injections Contains phospholipids from the soya beans

Retarpen 2.4 MIU - Powder and solvent for suspension for injection:

Povidone

Simethicone Sodium citrate Mannitol (E421).

1 vial of solvent contains: 5 ml water for injections Contains phospholipids from the soya beans

Data on compatibility are available with water for injections.

Store below 25 °C.

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

Solvent: Plastic vial made from polyethylene, nominal capacity 5 ml.

Retarpen 600,000 IU powder and solvent for suspension for injection:

4  ml clear glass vial, type III (Ph.Eur.), closed with halogenated butylrubber stopper and aluminium cap.

Packs with 1x powder and solvent for suspension for injection.

Retarpen 1.2 MIU powder and solvent for suspension for injection:

5 ml clear glass vial, type III (Ph.Eur.), closed with halogenated butylrubber stopper and aluminium cap.

Packs with 1x or 100x powder and solvent for suspension for injection.

Retarpen 2.4 MIU powder and solvent for suspension for injection:

15 ml clear glass vial, type III (Ph.Eur.), closed with halogenated butylrubber stopper and aluminium cap.

Packs with 1x or 50 x powder and solvent for suspension for injection.

Not all pack sizes may be marketed.

Retarpen 600,000 IU

For the IM injection, suspend the contents of the vial in at least 2 ml water for injections. This suspension should be shaken well for at least 20 seconds until suspended homogeneously and used immediately. If not used immediately shake the suspension again for at least 20 seconds until suspended homogeneously. The needle size should be at least 0.9 mm (needle no. 1). For single withdrawal only, use only freshly prepared suspensions. Prior to injection, intravascular  administration should be excluded by aspiration. The injection site should be changed with repeated injections.

Retarpen 1.2  MIU

For the IM injection, suspend the contents of the vial in at least 3 ml water for injections. This suspension should be shaken well for at least 20 seconds until suspended homogeneously and used immediately. If not used immediately shake the suspension again for at least 20 seconds until suspended homogeneously. The needle size should be at least 0.9 mm (needle no. 1). For single withdrawal only, use only freshly prepared suspensions. Prior to injection, intravascular  administration should be excluded by aspiration. The injection site should be changed with repeated injections.

Retarpen 2.4  MIU

For the IM injection, suspend the contents of the vial in at least 5 ml water for injections. This suspension should be shaken well for at least 20 seconds until suspended homogeneously and used immediately. If not used immediately shake the suspension again for at least 20 seconds until suspended homogeneously. The needle size should be at least 0.9 mm (needle no. 1). For single withdrawal only, use only freshly prepared suspensions. Prior to injection, intravascular  administration should be excluded by aspiration. The injection site should be changed with repeated injections.

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