Penilente La 1,2 MU and 2,4 MU Powder for Suspension

- Treatment of infections caused by organisms sensitive to penicillin: staphylococci (except penicillinase- producing strains), streptococci (Groups A, C, G, H, L, and M), and pneumococci, Corynebacterium diphtheriae, Bacillus anthracis, Clostridia species, Actinomyces bovis, Streptobacillus moniliformis, Listeria monocytogenes, and Leptospira species.

- Streptococcal pharyngitis (Grade A betahaemolytic streptococci infection).

- Syphilis (Neisseria gonorrhoeae, Treponema pallidum) of less than 1 year duration.

- Uncomplicated cases of erysipeloid (Erysipelothrix rhusiopathiae).

- Prophylactic use: recurrence of rheumatic fever.

Posology

Adults: Streptococcal pharyngitis and erysipeloid: 1,2 million units. Syphilis: 2,4 million units. Recurrence of rheumatic fever 1,2 million units.

Paediatric population

Children: 600 000 units to 1,2 million units. Should be administered by deep intramuscular injection once a month.

Method of administration

FOR INTRAMUSCULAR USE ONLY. Not for intravenous (IV) use. See section 6.6 for preparation of suspension.

Must not be administered to patients who are allergic to penicillin or cephalosporins or to any ingredient of PENILENTE LA. Babies in the neonatal period born to mothers allergic to penicillin.

Cases of cross-sensitivity to other beta-lactams have been reported. Should not be used in life-threatening conditions e.g., endocarditis, peritonitis or meningitis where very high doses of penicillin is indicated. Must not be administered intravenously (IV).

FOR INTRAMUSCULAR USE ONLY. PENILENTE LA should not be used in tissues with reduced perfusion. Before initiating therapy with PENILENTE LA, a careful investigation should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam medicines (see sections 4.3 and 4.8). Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous reactions) have been reported in patients on penicillin therapy (i.e., PENILENTE LA). Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction (see section 4.8). These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, PENILENTE LA must be discontinued and appropriate therapy instituted. When administered to a patient with penicillin allergy, anaphylactic shock may occur. Epinephrine (adrenaline), corticosteroids, antihistamines and appropriate IV fluids should be used to treat anaphylaxis (see section 4.3). Use with caution in patients with known history of allergy. 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);
• renal insufficiency;
• impaired hepatic function.

A generalised sensitivity reaction with urticaria, fever, joint pains and eosinophilia can develop within a few hours to several weeks after starting treatment. Based on a general principle, particularly in some exposed patients, medical observation should if possible be ensured for at least half an hour after the administration of this antibiotic, as severe immediate allergic reactions may occur even after the first administration. Beta-lactams are associated with a risk of encephalopathy (confusion, altered levels of consciousness, epilepsy or movement abnormalities), particularly in cases of over-dose or impaired renal function. Care should be taken when high doses are given to patients with renal impairment (because of the risk of neurotoxicity) or congestive heart failure. When treating syphilis, a Jarisch-Herxheimer reaction may occur as a result of the bactericidal action of penicillin on pathogens. This reaction can be dangerous in cardiovascular syphilis or where there is a serious risk of increased local damage such as with optic atrophy. Within 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). With long-term treatment (more than a single dose), periodic assessment of organ system functions, including renal, hepatic, and haematopoietic function is recommended. Prolonged use of PENILENTE LA may occasionally result in an overgrowth of non-susceptible organisms or yeast and patients should be observed carefully for superinfections. Superinfection by resistant species, such as Pseudomonas or Candida, which do not respond to penicillin therapy, may occur. Antibiotic-associated colitis has been reported with nearly all antibacterial medicines including PENILENTE LA and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic-associated colitis occur, benzathine benzylpenicillin (i.e., PENILENTE LA) should be discontinued, a medical practitioner be consulted, and an appropriate therapy initiated. Anti-peristaltic medicines are contraindicated in this situation. 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 benzylpenicillin should be considered.

Concomitant administration of PENILENTE LA is not recommended with:

• Bacteriostatic antibiotics: based on the general principle not to combine bactericidal and 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, probenecid inhibits the penicillin transport from the cerebrospinal fluid, so that the concomitant administration of probenecid reduces the penetration of benzylpenicillin into brain tissue even further.
• Methotrexate: when taken at the same time as PENILENTE LA, 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, such as warfarin and PENILENTE LA, 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 medicine adjusted accordingly, both during and after treatment with PENILENTE LA.

Pregnancy

Safety and/or efficacy during pregnancy has not been established.

Breastfeeding

Mothers on PENILENTE LA should not breastfeed their infants. Safety and/or efficacy during lactation has not been established.

Fertility

No fertility studies have been conducted in humans.

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

a. Summary of the safety profile

The most frequent and common adverse reactions related to benzathine benzylpenicillin (i.e., PENILENTE LA) are candidiasis, diarrhoea, nausea, and laboratory investigation changes.

b. Tabulated list of adverse reactions

MedDRA System Organ Class (SOC) Frequent Less frequent Frequency unknown

Infections and infestations Candidiasis.

Blood and lymphatic system disorders Leukopenia, thrombocytopenia, agranulocytosis. Haemolytic anaemia, neutropenia, prolongation of bleeding time, defective platelet function.

Immune system disorders Allergic reactions which may include exfoliative dermatitis, other skin rashes, and vasculitis, may occur. Angioedema, erythema multiform, arthralgia, anaphylactic shock with collapse and anaphylactoid reactions (asthma, purpura, gastrointestinal). Serum sickness, a generalised sensitivity reaction with urticaria, fever, joint pains and eosinophilia, superinfection by resistant species, Jarisch-Herxheimer reaction.

Cardiac disorders Kounis syndrome.

Gastrointestinal disorders Diarrhoea, nausea, stomatitis and glossitis, Heartburn, pseudo-membranous colitis (see section 4.4).

Hepato-biliary disorders Hepatitis, cholestasis, increases in liver enzyme values.

Skin and subcutaneous tissue disorders A sore mouth or tongue and a black hairy tongue. Linear immunoglobulin A (IgA) disease.

Renal and urinary disorders Nephropathy, interstitial nephritis.

General disorders and administration site conditions Pain at the injection site, injection site infiltrates, Hoignu00e9 syndrome, Nicolau syndrome.

Investigations 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 nonenzymatic urinary glucose detection and urobilinogen detection. Increased levels when determining 17 ketosteroids in urine (when the Zimmermann reaction is used) (see section 4.4).

c. Description of selected adverse reactions

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. In infants, local reactions are possible.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who- umc.org) found on SAHPRA website.

At extremely high doses, penicillins can induce neuromuscular excitability or epileptiform seizures. If overdose is suspected, supportive treatment and symptomatic measures are indicated. Benzylpenicillin can be haemodialyzed. In overdose, side effects can be precipitated and/or be of increased severity (see section 4.8).