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Procain Penicillin G Biotika Inj. Sicc. 1,5g

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT  


PROKAIN PENICILIN G 1,5 BIOTIKA



2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Drug substance: Procaini benzylpenicillinum monohydricum 600 000 IU, 1 500 000 IU, 3 000 000 IU or 4 000 000 IU in injection vial. 
100 000 IU contains 40 mg of bound procain.
Excipients: For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 
Powder for suspension for injection
Description: white crystalline powder, sparingly soluble in water, slightly soluble in alcohol.

4. CLINICAL PARTICULARS  

4.1. Therapeutic indications 
All indications of penicillin treatment. Procaine benzyl penicillin is intended for continuation of the treatment started with potassium salt of benzyl penicillin, but also for a separate application. Venerologic indications of procaine penicillin are complicated and uncomplicated gonorrhea and syphilis. 

4.2. Posology and method of administration 
The medicinal product is applied intramuscularly only.  

Dosage to children:

 InfectionsChildren younger than 1 year Children aged 1 – 5 years Children aged 6 -12 years
 light150 000 - 300 000 IU daily      
 (in 1 - 2 doses)
300 000 IU daily 
(in 1 - 2 doses)
600 000 IU daily 
(in 1 - 2 doses)
medium
severe
1 000 000 IU daily 
(in 1 - 2 doses)
2 000 000 IU daily 
(in 2 doses) 
2 000 000 IU daily 
(in 2 doses) 


Dosage to adults:

Infection Adults 
light 600 000 - 1000 000 IU daily (in 1 - 2 doses) 
medium severe 2 000 000 IU daily (in 1 - 2 doses) 
severe 4 800 000 IU daily (in 1 dose) 

Adults are administered 600 000 IU in light infections, 1 500 000 to 3 000 000 IU in medium severe infections intramuscularly. In severe infections induced by penicillin sensitive microbes, at the beginning of treatment the injection of benzyl penicillin potassium salt is applied and then procaine benzyl penicillin is applied. 
Children are applied 1 500 000 IU/m²/day or also 50 000 IU/kg/day in 1 – 2 doses.
For termination of treatment of streptococcal infection it is necessary to apply the injection of the medicinal product Pendepon or Pendepon Compositum.
Dosage in gonorrhea and syphilis:
Usual doses in the treatment of primary, secondary and tertiary stage on syphilis are 600 000 IU to 1 200 000 IU daily during 10 days. Therapy of latent phase of syphilis: 600 000 IU to 900 000 IU daily during 10 days. In treatment of neurosyphilis the recommended dosage is 600 000 IU to 900 000 IU daily during 15 to 20 days. In congenital manifesting syphilis also to asymptomatic children 50 000 IU / kg of body weight during 10 days, in neurological complications 50 000 IU / kg of body weight daily during 10 to 14 days.
In treatment of acute uncomplicated gonorrhea 1 dose of 4 800 000 IU 30 minutes after previous dose of probenecid of 1 g (procaine penicillin is applied in two doses at two sites). Prevention of gonorrhea and syphilis: 4 800 000 IU within 2 hours after exposition.

4.3. Contraindications 
Absolute contraindication is hypersensitivity to penicillin or cephalosporins and to procaine.
In regard to the fact that the application form is a suspension, the intravenous application is absolutely prohibited!
Caution is necessary in application of the medicinal product to the patients with any allergy and in bronchial asthma also in anamnesis. 

4.4. Special warnings and precautions for use 
Administration of procaine penicillin to risk groups:
Newborns – besides the necessity to reduce the dose no other restrictions are known.
Pregnancy – the safety of administration is proven in long-time administration.
Elderly patients – besides adjusting the dosage to a condition of renal functions there are no other restrictions.
In anaphylactic shock it is necessary to get the circulation failure and potential breathing disorders under control using adrenaline, noradrenaline, hydrocortisone, to apply antihistamines and calcium. Further it is necessary to follow the principles of how to overcome these reactions.

4.5. Interactions with other medicinal products or other forms of interaction 
In concomitant application of bacteriostatic antibiotics (tetracyclines, chloramphenicol, erythromycin etc.) the mutual antagonism occurs. Procaine penicillin decreases the effect of per oral anticoagulants; its effect is decreased by chlorpromazine; level of penicillin in blood is increased by concomitant application of salicylates, aminophenazone and vitamin C. Procaine released from procaine penicillin may interfere by laboratory determination of 17-hydroxysteroides and 17-ketosteroids what causes distortion of the results. Procaine increases effect and toxicity of antiarrhythmics, vasodilatations. In concomitant administration it interrupts the effect of sulfonamides. Toxicity of procaine in increased by inhibitors of cholinesterase, morphine, ephedrine. Similarly the administration of procaine penicillin can influence the results of thyroid gland examination. 

4.6. Pregnancy and lactation 
In usual doses procaine benzyl penicillin is not contraindicated in pregnancy, puerperium, neither in lactation. Benzylpenicillin passes placenta and the level in serum of fetus reaches the levels close to the levels in serum of mother. Present experiences with application to pregnant women and also testing in rats, rabbits and monkeys have not proven any evidence of teratogenicity. In first trimester however it is applied only if it is necessary. Penicillin is excreted into breast milk, the levels reach 2 – 15 % of serum concentration. This can be a reason of sensibilization (allergic reactions), more often however it is influence of physiological intestinal flora of child. 

4.7. Effects on ability to drive and use machines 
In higher dosage (more than 4 000 000 IU) the adverse effects of procaine may appear. The intensity depends on the reached plasmatic level. These are particularly the effects in the area of CNS: discomfort, shiver or even shaking of limbs, vision impairments, tinnitus, somnolence, hyporeflexion. Therefore the doctor should warn the patient of this fact.

4.8. Undesirable effects 
Allergic reactions occur much more often in persons with allergic disposition. The most serious is anaphylactic reaction which appears 1 – 2 minutes after application (sometimes also within half an hour or even later) as collapse or even cardio-respiratory failure which could lead up to a lethal ending. Other allergic symptoms are urticaria, fever, pain in joist, angioneurotic edema, Lyell´s or Stevens-Johnson syndrome. Occurrence of nausea, vomiting, diarrhea; hemorrhage; hemolytic anemia, eosinophilia, thrombocytopenia; very rarely cholestatic jaundice and lupus erythematodes is possible. In treatment of syphilis even in 50 % of cases occurs Jarisch-Herxheimer reaction, which is shown by fever, sweating, headache up to collapse (consequence of endotoxins release). In cardio-vascular syphilis this reaction can have a very heavy process (primary atrophy n. optici, nervous deafness) and may be finished also lethally.
If in parenteral application the suspension of procaine benzyl penicillin penetrates into blood, Hoigne´s syndrome may occur, which has a rapid start, but a benign process. It is shown mostly by psychic experiences (fear of death, auditory and visual color hallucinations, confusion, disorientation), dizziness, taste disorders, tachycardia, palpitation of heart. Complications usually disappear within 30 minutes and are treated symptomatically. After intravasal injection in children Nicolau syndrome can occur. Early symptoms: sudden skin ischemia distally from injection site, partially with livid coloration and pain. Late symptoms: slight paralysis, ischemic necrosis, intestinal and renal bleeding. Besides local findings conditioned by ischemia (e.g. pain, paleness, formation of edema and pustules with subsequent necrotization) it is not possible to exclude a more difficult process demonstrated by shock and coagulopathy. Without any delay 300 IU/kg of heparin has to be applied i.v., or i.m. if necessary. Without any delay it is necessary to notify the specialized workstation of thrombolytic therapy. In prevention of both symptoms it is necessary to apply the correct application procedure (change of injection site, needle with sufficiently big lumen, aspiration and fixation in injection site). Patient should be kept under medical supervision at least 30 minutes after the application.
In application of high doses the toxic effects of procaine may occur; the intensity depends on the reached plasmatic level. These are mainly the effects in the area of CNS: discomfort, shiver or even shaking of limbs, vision impairments, tinnitus, somnolence, hyporeflexion, in the area of cardio-vascular system: bradycardia, hypotension in severe case may lead up to asystolic circulation blockage. 

4.9. Overdose 
Procaine benzyl penicillin is an antibiotic agent with very low toxicity. LD50 of benzyl penicillin in mice and rats is higher than 5 000 mg/kg what can be considered to be a non-toxicity. The symptoms of indirect toxicity are the changes of normal bacterial flora with over-reproduced penicillin-resistant micro-organisms with super-infection symptoms. Its occurrence is lower than in broad-spectral antibiotics. 
After application of high doses (e.g. in gonorrhea 4 800 000 IU) procaine may reach toxic levels.
In light cases the overdose may be restored well by application of diazepam i.v. In severe cases it is necessary to apply myorelaxans, to ensure artificial ventilation and in case of a collapse to ensure a complex cardio-pulmonary-cerebral resuscitation. 


5. PHARMACOLOGIC PROPERTIES 

Pharmacotherapeutic group: antibiotic agent
ATC code: J01CE09

5.1. Pharmacodynamic properties 
Procaine benzyl penicillin is a sparingly soluble ester of benzyl penicillin with procaine (100 000 IU of procaine benzyl penicillin contains 40 mg of bound procaine). Solubility in water is 1 : 200 and in alcohol 1 : 10. It is a penicillin bactericidal antibiotic with long-term effect. It is applied intramuscularly. Mechanism of action is identical with other penicillins, it inhibits transpeptidation of peptidoglycan what destroys synthesis of murein. The consequence is destroyed cell wall with subsequent death of bacteria. 
A n t i m i c r o b i a l   s p e c t r u m : identical with Penicillin G. 
It has a very good action on pyogenic and other hemolytic streptococci, pneumococci, gonococci and meningococci, corynebacteria, listeria, Erysipelothrix insidiosa, bacillus of anthrax, actinomyces, clostridia of tetanus and anaerobic traumatosis, moraxella, Treponema pallidum and on most leptospira strains. It has a lower action against viridating streptococci (70 – 80 % of strains), enterococci (only 20 – 40 % of strains) and from staphylococci only against the strains which do not produce penicillinase (about 15 % of strains). If the higher concentrations are reached (in serum by application of higher doses, in urine also by usual doses), benzyl penicillin acts also on some gram-negative intestinal sticks, e.g. on Escherichia coli, suspiginous forms of proteus and salmonella. This effect can be used clinically, for example for treatment of some infections of urinary tract. Insensitive are pseudomonades, brucella, francisela, bordetella, haemophili (except H. haemolyticus) and mycobacteria, mycoplasma, rickettsias, bedsonias, fungi and protozoa. 

5.2. Pharmacokinetic properties 
Procaine penicillin is instable in acid stomach environment, hydrolysis of beta-lactam occurs. Absorption from gastrointestinal tract is not regular, therefore it is applied intramuscularly only. After intramuscular application it is absorbed slowly from muscle and maximum plasma level is reached in about 2 hours (1 – 4), then it decreases slowly. Effective level may be proved even 24 hours after application. 

Approximate concentrations of procaine penicillin in serum (in IU / mL) after administration of different substances 

Dose IU

0.5 h

1 h

2 h

4 h

6 h

12 h

16 h

24 h

       300 000

 

1.5

 

 

 

0.33

 

0.2

       400 000

 

5

0.9

0.8

 

0.48

 

 

       600 000

2.7

2.65

2.32

2.1

0.5

0.66

0.2

0.16

    1 200 000

 

 

 

 

 

0.96

 

 

    2 000 000

 

 

 

 

 

3.14

 

 

    2 400 000

 

 

 

 

 

1.92

 

 

    4 000 000

 

 

 

 

 

1.92

 

 


After application benzyl penicillin is released from procaine penicillin. It is distributed to the whole body, penetrates into pericardial and pleural cavity, bile and saliva. It passes through placental barrier and into breast milk. It penetrates primary to the places where the inflammatory processes are running and here the higher concentrations are reached than in the places without inflammation. In meningitis the high concentrations are reached in brain. Passage through non-flamed meninges is very low, in order to reach therapeutic concentrations in cerebrospinal liquor at the treatment of lues it is therefore combined with probenecid. It does not penetrate into bones. It penetrates insufficiently into purulent foci, into ischemic areas and necrotic tissues. Procaine benzyl penicillin is not soluble in lipids, therefore it does not enter the cells. 50 – 65 % is bound to plasmatic proteins. From an organism it is excreted by kidneys, mostly by tubular secretion, but more slowly than potassium salt of benzyl penicillin. Inhibitor of tubular secretion probenecid prolongs half-life of elimination of procaine penicillin and increases its plasmatic concentration. Excretion of procaine penicillin is not dependent on size of applied dose. 


6. PHARMACEUTIC PARTICULARS

6.1. List of excipients 
Lecithinum

6.2. Incompatibilities 
Suspension of procaine penicillin is incompatible with solution of procaine. 

6.3. Shelf life 
3 years

6.4. Special precautions for storage 
Store below 25 °C, on dry place, protect from light. 
Keep out of reach and sight of children.

6.5. Nature and contents of container 
Injection vial with crimp and stuck label, rubber stopper with aluminium crimp, box 
Package size:  

1, 10 and 50 injection vials of  600 000 IU
1, 10 and 50 injection vials of  1 500 000 IU
1, 10 and 50 injection vials of  3 000 000 IU
1, 10 and 50 injection vials of  4 000 000 IU
Not all pack sizes may be marketed. 

6.6. Special precautions for disposal and other handling 
Before application a suspension has to be prepared from the medicinal product. From the vial the scotched part of aluminium cap is teared down and the rubber stopper is cleaned with 70% alcohol or mixture of alcohol with ether. Injection syringe and needle for application have to be clear of alcohol. Water for injection is added into the vial according to the following table:

 Content of vial (IU)
Volume of added water 
for injection in mL
Concentration of penicillin in suspension 
(IU/mL) 
 600 000 1,8300 000 
1 500 000 4,5300 000 
3 000 000 5,0500 000 
4 000 000 8,0 400 000 

After dilution the suspension is mixed thoroughly. Using the same syringe and needle the volume intended for the application is drawn into syringe, while the vial is held neck downwards. Excessive volume and air are pushed from syringe to vial and a new needle is used for the application. In such a way the leak of penicillin aerosol into air, which could sensitize the medical staff and patients, is avoided. After drawing into syringe the suspension has to be injected immediately with a stronger needle intended for application into muscle to the upper outside quadrant of M. glutaeus maximus. In repeated application it is necessary to change the application sites. It is recommended not to apply more thank 5 mL of the prepared suspension at one application site. 

7. MARKETING AUTHORISATION HOLDER 

BB Pharma a.s., Pod Višňovkou 1662/21, Prague, Czech Republic

8. MARKETING AUTHORISATION NUMBER

15/0158/69-S, 15/1096/94-C 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
1969 /  
10. DATE OF REVISION OF THE TEXT 
September 2013