Package leaflet: Information for the user

Tarlidocin

1.2 million IU/25 mg
Powder and solution for injectable suspension
benzathine benzylpenicillin/lidocaine hydrochloride monohydrate
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Tarlidocin is and what it is used for
What you need to know before using Tarlidocin
How to use Tarlidocin
Possible side effects
How to store Tarlidocin
Contents of the pack and other information

1. What Tarlidocin is and what it is used for

Tarlidocin contains 1 vial of powder with the active substance benzathine benzylpenicillin and
1 vial of solution with the active substance lidocaine hydrochloride monohydrate.
Tarlidocin is an antibiotic administered to adults and children. It contains a depot penicillin,
given by intramuscular injection for the treatment of bacterial infections.
Tarlidocin is used to treat:

erysipelas (skin infection, only as follow-up treatment following initial intravenous antibiotic therapy, after improvement of local signs and symptoms and permanent resolution of fever)
syphilis
infectious tropical skin diseases caused by bacteria of the Treponema species, such as yaws or pinta

Tarlidocin is also used for the prevention of the following diseases:

rheumatic fever
post-streptococcal glomerulonephritis (a specific form of kidney inflammation)
erysipelas (skin infection)

This medicine contains a local anaesthetic agent (lidocaine hydrochloride monohydrate,
referred to as lidocaine in the remainder of this leaflet) to reduce the initial pain of the injection.

2. What you need to know before using Tarlidocin

Do not use Tarlidocin

if you are allergic to benzathine benzylpenicillin or lidocaine, other penicillins, certain local anesthetics of the acid amide type, soy, peanuts, or to any of the other ingredients of this medicine (listed in section 6)
if you have previously been treated with other penicillin-containing products and developed a hypersensitivity reaction (e.g., skin rash, itching, fever, shortness of breath, reduced blood pressure) to those medicines, as there is a risk of potentially life-threatening anaphylactic shock
if you are known to be hypersensitive to other beta-lactam antibiotics (e.g., cephalosporins, carbapenems), with the exception of monobactams (aztreonam), due to the possibility of cross-allergy
if you have complete heart block (an abnormal heart rhythm occurring when electrical impulses controlling heartbeat are blocked)
for treatment of neonates with congenital syphilis (acquired before birth)

Warnings and precautions
Talk to your doctor or pharmacist before Tarlidocin is administered to you

if you have previously experienced allergic reactions to other antibiotics such as penicillin or other beta-lactam antibiotics
if you have kidney problems (your doctor may need to adjust the dose of the medicine)
if you have liver problems

Tarlidocin must not be used in tissues with poor blood supply.
If allergic symptoms occur (e.g., skin rash, itching, shortness of breath), consult your doctor immediately. If an allergic reaction occurs, your doctor will discontinue treatment and, if necessary, initiate appropriate therapy.
Since cross-allergy is possible in patients hypersensitive to cephalosporins and carbapenems, inform your doctor if you have previously had an allergic reaction to certain antibiotics (cephalosporins, carbapenems).
You must inform your doctor if you have ever been diagnosed with an allergy and/or allergic asthma or hay fever. Severe immediate allergic reactions may occur even upon first administration of the drug. According to general principles, especially in certain cases, you should remain under observation for at least one hour after administration of the medicine, in case an acute allergic reaction occurs. If an allergy develops, your doctor will take appropriate measures. Treatment with Tarlidocin must be stopped immediately.
During treatment of syphilis, a bodily reaction to bacterial toxins may occur, lasting for several days (Jarisch-Herxheimer reaction, see section 4). Typical symptoms include sudden fever (sometimes with chills), pallor followed by skin flushing, headache, painful muscles and joints, or fatigue. To suppress or alleviate a Jarisch-Herxheimer reaction, your doctor will initiate appropriate therapy.
If you experience severe watery diarrhea during or after treatment, possibly accompanied by fever or abdominal pain, consult your doctor immediately, as this may be caused by a serious intestinal disease (pseudomembranous colitis).
Prolonged and repeated use may lead to overgrowth of bacteria and yeasts not sensitive to the drug.
During long-term treatment, your doctor may arrange for regular blood count and kidney function tests. You must ensure you attend all scheduled check-ups.
Allergic reactions may occur in patients with dermatomycosis (fungal skin infection) after the first administration of Tarlidocin, due to shared antigenicity between penicillin and dermatophytes (fungi causing skin infections).
If neurological involvement cannot be ruled out in patients with congenital syphilis, forms of penicillin capable of achieving higher levels in cerebrospinal fluid should be used.
Reduced elimination of povidone (one of the excipients of this medicine) should be considered in case of impaired renal function. It cannot be excluded that, in very rare cases, accumulation of povidone or local deposition may occur, leading to granuloma formation, which could be mistaken for tumors.
An effect on laboratory diagnostic tests should also be considered (see also section 4).
Since the medicine contains lidocaine, Tarlidocin must be used with particular caution in patients with:

kidney and/or liver disease
myasthenia gravis (a condition that may cause muscle weakness)
a lowered threshold of the central nervous system for seizures (e.g., epilepsy)
cardiac disorders, including cardiac conduction disorders
slow heart rate
respiratory depression (difficulty breathing, shallow and slow breathing)
poor general health or elderly patients

Toxic embolic reactions, probably due to vascular occlusion by large crystals of penicillin salts, may be exacerbated by the lidocaine contained in this medicine (Hoigne's and Nicolau's syndrome).
Treatment with Tarlidocin should be avoided in patients with a disorder of red pigment biosynthesis that gives blood its color (porphyria), due to the lidocaine contained in this medicine.
Tarlidocin must be used with particular caution in patients with bleeding disorders or those being treated for such disorders, or those receiving non-steroidal anti-inflammatory drugs or plasma substitutes, as accidental injury to blood vessels may cause severe bleeding.

Other medicines and Tarlidocin
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. Benzathine benzylpenicillin may interact with or be affected by other medicines.
Caution is required when administering Tarlidocin concurrently with the following medicines:
probenecid and sulfinpyrazone, medicines used in the treatment of gout
salicylates, medicines used to reduce pain or prevent blood clots
indomethacin and phenylbutazone, medicines used to reduce pain
methotrexate, a medicine used in chemotherapy. Combination with methotrexate is not recommended
anticoagulants, medicines used to thin the blood

Lidocaine may interact with or be affected by other medicines. In particular, inform your doctor if you are taking any of the following medicines:
medicines used to treat heart conditions, including irregular heartbeat, such as beta-blockers or calcium channel blockers
medicines that constrict blood vessels (vasoconstrictors, e.g., epinephrine or norepinephrine)
other anesthetics, including local anesthetics
sleeping pills and medicines that reduce the level of consciousness (sedatives)
medicines used to relax muscles (non-depolarizing muscle relaxants)
medicines that increase the risk of seizures (e.g., tramadol, bupropion)
medicines that reduce the risk of seizures (e.g., diazepam)

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine.

Pregnancy
Data on the use of benzathine benzylpenicillin and lidocaine, the pharmacologically active components of Tarlidocin, in pregnant women are insufficient. Therefore, Tarlidocin should be used during pregnancy only if absolutely necessary.

Breastfeeding
Benzylpenicillin and lidocaine are excreted in breast milk.
When Tarlidocin is used during breastfeeding, sensitization and interference with normal intestinal bacterial flora in the infant cannot be excluded.
The infant should be monitored for signs of diarrhea and mucosal colonization by yeasts.

Driving and using machines
Given that this medicine contains lidocaine, it cannot be excluded that, in individual cases, the ability to drive (active participation in road traffic), operate machinery, or work at heights may be impaired for a short period after injection.
Therefore, your doctor must decide whether, in your particular case, you may drive (actively participate in road traffic) or operate machinery.

Tarlidocin contains povidone
Delayed excretion of povidone should be considered in patients with impaired renal function. Since this medicine contains povidone, it cannot be excluded that frequent or prolonged use, in very rare cases, may lead to accumulation of povidone in the reticuloendothelial system (RES) or local deposits and formation of foreign-body granulomas, which could be mistaken for tumors.

Tarlidocin contains sodium
This medicine contains 26.19 mg of sodium per 1.2 million IU dose. This is equivalent to 1.3% of the maximum daily dietary intake recommended for an adult.

3. How to use Tarlidocin

Tarlidocin is generally administered by a healthcare professional. If you have any doubts about
how this medicine is administered, consult your doctor or pharmacist.
The recommended dose is:
General treatment (e.g., follow-up treatment of erysipelas):
Adults and adolescents: 1.2 million IU once weekly
Children > 30 kg body weight: 1.2 million IU once weekly
Children 3.5 kg–30 kg body weight: 600,000 IU once weekly
Treatment of syphilis:
Primary and secondary stage
Adults and adolescents: 1 x 2.4 million IU
Children: 50,000 IU/kg body weight, but not exceeding 2.4 million IU
Treatment should be repeated if clinical symptoms recur or if laboratory results remain strongly positive.
Duration of treatment: single dose
Late-stage syphilis (seropositive latent syphilis)
Adults and adolescents: 2.4 million IU once weekly
Children: 50,000 IU/kg body weight, but not exceeding 2.4 million IU
Duration of treatment: 3 weeks
Treatment of congenital syphilis: without neurological involvement
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 million IU
Children > 30 kg body weight: 1 x 1.2 million IU
Children 3.5 kg–30 kg body weight: 1 x 600,000 IU
Duration of treatment: single dose
Prophylaxis of rheumatic fever, post-streptococcal glomerulonephritis, and erysipelas:
Adults and adolescents: 1 x 1.2 million IU every 2–4 weeks
Children > 30 kg body weight: 1 x 1.2 million IU every 3–4 weeks
Children 3.5 kg–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 until age 21
b) transient cardiac involvement: at least 10 years or until age 21
c) persistent cardiac involvement: at least 10 years or until age 40; sometimes lifelong prophylaxis is required.
Special patient groups (with kidney or liver problems or heart failure)
Dose and frequency of administration will be determined by the doctor. If you need clarification on
dosing, consult your doctor.
Use in children
Tarlidocin must not be used in children with body weight below 3.5 kg to avoid exceeding the maximum dose of lidocaine.
Tarlidocin should be used with particular caution in children under 4 years of age due to its lidocaine content.
Method of administration
For intramuscular use only (the preparation may be injected only into muscle)
Tarlidocin is not suitable for subcutaneous, intravascular, or spinal canal injection.
With repeated intramuscular administration, the injection site should be rotated.
Severe local reactions may occur during intramuscular administration, particularly in young children. For this reason, alternative treatments, such as a different penicillin formulation, may be considered if possible.
Important information for physicians/healthcare professionals regarding the method of administration is
provided at the end of this leaflet.
If you use more Tarlidocin than you should
At extremely high doses, penicillins may cause neuromuscular excitability or epileptic-like seizures. If overdose is suspected, seek immediate medical advice.
An overdose of lidocaine primarily affects the central nervous system. If you begin to experience dizziness or mental confusion, numbness of the tongue, tinnitus, vomiting, or tremors, inform the person administering the injection immediately. The doctor will know how to manage these symptoms and will provide any necessary treatment.
Important information for physicians/healthcare professionals regarding symptoms of overdose or misuse is provided at the end of this leaflet.
If you forget to use Tarlidocin
If you think a dose has not been administered, inform your doctor immediately.
If you stop using Tarlidocin
Do not stop treatment with Tarlidocin without first consulting your doctor. Otherwise, there is a risk that your illness may not be fully cured and that you may experience a relapse.
If you have any doubts about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
Important side effects to be aware of:
Severe allergic reaction (may affect up to 1 in 10,000 people)
If you have a severe allergic reaction (anaphylaxis), inform your doctor immediately.
Signs may include: shock with circulatory failure, sweating and impaired consciousness (potentially life-threatening, see also section 2 "Warnings and precautions").
Severe skin reactions
If you experience a severe skin reaction, inform your doctor immediately.
Signs may include:

Very rare (may affect up to 1 in 10,000): skin rash with blisters, usually involving mucous membranes (Stevens-Johnson syndrome, toxic epidermal necrolysis)
Frequency not known: increase in the number of certain blood cells due to hypersensitivity (eosinophilia), hives causing intense itching (urticaria), swelling of the skin and mucous membranes, particularly of the face, mouth, throat and larynx (angioedema), inflammation of blood vessels with bleeding into the skin and mucous membranes (leukocytoclastic vasculitis, Henoch-Schönlein purpura), painful skin nodules (erythema nodosum). Any immediate-type reaction with hives causing intense itching (urticaria) must always be considered a serious sign and requires strict discontinuation of therapy.

Benzylpenicillin may cause the following side effects:
Common (may affect up to 1 in 10)

hypersensitivity reactions (it is impossible to estimate the frequency of individual allergic reaction symptoms accurately based on available data)
skin rash (morbilliform or scarlatiniform)
hardening at the injection site, fever
Changes in certain laboratory tests and investigations, such as: positive direct Coombs test false positive results in tests to detect the presence of proteins in urine using precipitation techniques (Folin-Ciocalteu-Lowry method, biuret method) false positive results in tests to detect the presence of proteins in urine (ninhydrin method) simulation of pseudobisalbuminemia [transient changes in blood protein (albumin) properties] when electrophoresis methods are used to determine albumin false positive results in non-enzymatic tests to detect glucose and urobilinogen in urine increased levels during determination of 17-ketosteroids (using Zimmermann reaction) in urine (see section 2)

Uncommon (may affect up to 1 in 100)

inflammation of the tongue and oral mucosa, black hairy tongue, feeling unwell (nausea), sickness (vomiting), diarrhoea

Rare (may affect up to 1 in 1,000)

severe watery diarrhoea during or after treatment, which may be accompanied by fever or abdominal pain, caused by a serious intestinal disease (pseudomembranous colitis) (see also section 2 "Warnings and precautions")
serum sickness (symptoms include, but are not limited to, fever, joint swelling and skin rash)
kidney disease (nephropathy), inflammation of the kidneys (interstitial nephritis)

Very rare (may affect up to 1 in 10,000)

certain blood disorders (so-called haemolytic anaemia, leucopenia, thrombocytopenia, agranulocytosis)
liver cell damage, blockage of bile flow. These reactions have occurred in association with shock, rash, exfoliative dermatitis, fever and/or increase in the number of certain blood cells due to hypersensitivity (eosinophilia) or serum sickness syndrome
Not known (frequency cannot be estimated from available data)
infections with resistant bacteria and fungal infections (candidiasis)
allergic swelling, Jarisch-Herxheimer reaction (this reaction may occur during treatment of syphilis (usually 2–12 hours after administration of the first dose) and is characterised by fever, chills, general and focal symptoms)
blockage of blood vessels (arteries)
swelling of the larynx, spasmodic narrowing of the bronchi with laboured breathing, allergic lung disease (pulmonary eosinophilia)
toxic embolic reactions, probably due to vascular occlusion by large crystals of penicillin salts (Hoigne and Nicolau syndromes), pain at the injection site, which may occur even if the injection is administered correctly. The local anaesthetic agent contained in this medicine initially provides pain relief. Once the analgesic effect wears off, pain may persist for some time.

Other side effects/additional information
Neurotoxic reactions, which are possible with high-dose penicillin therapy, do not occur because the blood levels achieved with Tarlidocin are low.
Lidocaine may cause the following side effects:
Due to the low lidocaine content and the low frequency of use of Tarlidocin, the risk of dose-related systemic adverse reactions to lidocaine is low when the product is used as intended. Despite the low lidocaine content (the active analgesic ingredient), care must be taken regarding lidocaine's side effects. Reactions affecting the whole body may occur, for example after accidental intravenous injection.
Rare (may affect up to 1 in 1,000)

allergic reactions

Not known (frequency cannot be estimated from available data)

dizziness, mental confusion, convulsions (seizures), tingling around the mouth, tongue numbness, drowsiness
abnormally slow heartbeat, changes in heart rhythm, arrest of normal blood circulation due to heart failure, cardiac arrest, slight increase in blood pressure, low blood pressure, circulatory shock
respiratory depression
nausea, vomiting
skin rash, oedema

This medicine contains phospholipids from soybean seeds ((3-sn-phosphatidyl)choline); caution is required due to the risk of allergic reactions.
It is impossible to exclude, in very rare cases and considering the povidone content, the possibility of povidone accumulation in the reticuloendothelial system (RES) or local deposits and the appearance of foreign body granulomas, which could be mistaken for tumours.
Important information for physicians/healthcare professionals regarding potentially severe side effects in case of accidental intravascular injection is reported at the end of this leaflet.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You may also report side effects directly via
Website: www.aifa.gov.it/content/segnalazioni-reazioni-avverse .
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Tarlidocin

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label of the vial and on the
carton after "Exp.". The expiry date refers to the last day of that month.
Store in the original packaging to protect the medicine from light.
The reconstituted injectable suspension must be freshly prepared immediately before use.
Do not dispose of any medicine via wastewater. Ask your pharmacist how to
dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Tarlidocin contains

The active substances are benzathine benzylpenicillin and lidocaine hydrochloride monohydrate.

1 vial of powder contains 916.7 mg of benzathine benzylpenicillin (as tetrahydrate),
equivalent to 1,200,000 IU of benzathine benzylpenicillin.
1 glass vial of 5 ml solution contains 25 mg of lidocaine hydrochloride monohydrate.

The other components in the powder vial are: povidone K17, soybean lecithin, polysorbate 80, sodium citrate (anhydrous), citric acid, mannitol (E421), simethicone.
The other components in the solution vial are: sodium hydroxide, water for injections.

Description of the appearance of Tarlidocin and contents of the pack
Tarlidocin consists of a vial containing a white to cream-coloured powder and a vial containing a clear, colourless solution.
After reconstitution, the ready-to-use medicinal product is a homogeneous, milky-white injectable suspension.
Tarlidocin is available in packs containing 1 vial and 1 ampoule, and in multiple packs containing 5 boxes each with 1 vial and 1 ampoule.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
INFECTOPHARM Arzneimittel und Consilium GmbH
Von-Humboldt-Str. 1
64646 Heppenheim
Germany

This medicinal product is authorised in the European Economic Area Member States under the following names:
Austria: Tarlidocin
France: Tarlidocin
Germany: Tarlidocin
Netherlands: Tarlidocin
United Kingdom: Cindolin

The following information is intended exclusively for physicians or healthcare professionals:

Method of administration
The preparation is strictly for intramuscular injection only. The injection must not be administered into tissues with reduced perfusion.

Reconstitution of the injectable intramuscular suspension
The powder in one vial must be reconstituted with the solution from the ampoule.
To open the glass ampoule, the top must be broken at the score line on the neck of the ampoule.
Use a sterile syringe fitted with a needle to completely withdraw the solution from the ampoule.
To reconstitute the injectable suspension, insert the needle of the syringe through the rubber stopper of the vial so that the tip of the needle remains only in the upper part of the vial.
Then inject the solution completely and slowly into the vial, which should be gently rotated to mix. Avoid vigorous shaking of the vial.
The above procedure helps prevent leakage of the solution or foam formation.
The ready-to-use medicinal product is a homogeneous, milky-white injectable suspension. After reconstitution with the solution provided in this pack, the volume of the ready-to-use injectable suspension is 6 ml.

Administration of 1.2 million IU (equivalent to 1 vial)
The entire contents of one vial must be completely withdrawn and administered.

Administration of lower doses, e.g. 600,000 IU (equivalent to ½ vial)
The entire contents of one vial must be completely withdrawn. Half of the contents must be immediately discarded, and the second half administered.
The injectable suspension is for single use only. The product must be used immediately after opening the ampoule and reconstituting the suspension.
Any unused portion remaining after administration of the single dose must be discarded.

Injection
Using a long, large-bore needle (cannula diameter 0.90 mm), Tarlidocin must be administered via deep intramuscular injection into the upper-outer quadrant of the buttock, directed toward the iliac crest, or using the von Hochstetter technique. The needle should be inserted as perpendicularly as possible to the skin, and the injection should be performed as far as possible from major blood vessels. Always aspirate before injecting. The injection must be stopped immediately if blood is aspirated or if the patient experiences pain during injection.

In children, the recommended injection site is the mid-lateral thigh muscles (quadriceps femoris muscle). The deltoid muscle is suitable only if well-developed; in this case, care must be taken to avoid the radial nerve.

In infants and young children, the upper-outer quadrant of the gluteal region should be selected as the injection site only in exceptional cases (e.g., extensive burns), to avoid injury to the sciatic nerve.

The injection must not be administered into tissues with reduced blood flow (see also section 2 "Do not use Tarlidocin"). In case of repeated administration, the injection site must be changed.

The injection should be performed as slowly as possible and with only slight pressure. Massage of the injection site must be avoided.

Severe local reactions may occur during intramuscular administration, particularly in young children. Whenever possible, taking into account the specific therapeutic indications, dosing regimens, and benefit-risk assessment, alternative treatments such as intravenous therapy with an appropriate penicillin-based product should be considered.

During long-term treatment with depot penicillins (e.g., for the treatment of syphilis), repeated injections into a very limited area of muscle tissue may lead to tissue trauma and proliferation of blood vessels, thereby increasing the likelihood that the injected material enters the circulation—either via direct injection into a blood vessel, or by being forced into circulation due to injection pressure, or even by diffusion of the deposit due to massage. Therefore, during long-term treatment, each injection should be administered as far as possible from the previous injection site.

Note
Due to the risk of adverse reactions (Nicolau syndrome or Hoigné syndrome in association with the effects of lidocaine), it is absolutely essential to exclude intravascular placement of the needle by performing an aspiration test using an empty injection syringe.
The injection must be stopped immediately if blood is aspirated or if the patient experiences pain during injection.

Tarlidocin is not indicated for subcutaneous, intravenous, or intrathecal injections.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Symptoms of overdose/improper use
At extremely high doses, penicillins may cause neuromuscular excitability or epileptiform convulsive seizures. If overdose is suspected, clinical monitoring and symptomatic measures are indicated.

Lidocaine intoxication following inappropriate administration of an excessive amount of lidocaine manifests in two phases. Initially, patients may exhibit central and cardiac excitatory symptoms: agitation, restlessness, dizziness, visual and auditory disturbances, perioral tingling, slurred speech, nausea, vomiting, tremors, and muscle contractions, which may be signs of an impending convulsive seizure. Cardiovascular symptoms may include arrhythmia, tachycardia, hypertension, and flushing. As intoxication progresses, patients may develop central and cardiac depression, leading to coma, respiratory arrest, and circulatory arrest. Hypotension is a frequent prodrome. Accidental intravascular administration of lidocaine does not always produce excitatory symptoms. Acidosis, hyperkalaemia, hypocalcaemia, and hypoxia increase and prolong the toxic effects of local anaesthetics.

Emergency procedures and antidotes
Benzathine benzylpenicillin is haemodialysable.

At the first signs of lidocaine overdose, administration of Tarlidocin must be stopped immediately. Oxygen administration is recommended. Additional treatment should be symptomatic, based on the signs of intoxication: a convulsive seizure requires intravenous diazepam, while respiratory and circulatory arrest must be managed according to standard cardiopulmonary resuscitation procedures.

Central analeptic agents are contraindicated in local anaesthetic intoxication.