Cindolin 1.2 million IU/ 25 mg powder and solution for suspension for injection – patient leaflet, side effects, dosage

1. What Cindolin is and what it is used for

<Trade name> contains 1 vial of powder with the active substance benzathine benzylpenicillin and 1 ampoule of solution with the active substance lidocaine hydrochloride monohydrate.

Cindolin is an antibiotic given to adults and children. It contains a depot penicillin which is administered by injection into a muscle for the treatment of bacterial infections.

Cindolin is used for the treatment of:

• erysipelas (skin infection, follow-up treatment after initial intravenous antibiotic therapy only, when local signs and symptoms have improved and fever has permanently disappeared)
• syphilis
• tropical infectious diseases of the skin, caused by bacteria of the Treponema species, such as yaws, or pinta

Cindolin is also used to prevent the following diseases:

• rheumatic fever
• poststreptococcal glomerulonephritis (a specific form of kidney inflammation)
• erysipelas (skin infection)

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

2. What you need to know before you use Cindolin

Do not use Cindolin:

• if you are allergic to benzathine benzylpenicillin or lidocaine, other penicillins, certain local numbing agents (acid amide-type local anaesthetics), soya, peanut or any of the other ingredients of this medicine (listed in section 6)
• if you have previously been treated with other penicillin products and developed hypersensitivity reactions (e.g. skin rashes, itching, fever, shortness of breath, drop in blood pressure) to those medicines, since there is a risk of life-threatening anaphylactic shock
• if you know you are hypersensitive to other beta-lactam antibiotics (e.g. cephalosporins, carbapenems), except for monobactams (aztreonam), since there is a possibility of cross-allergy
• if you have a complete heart block (an abnormal heart rhythm that happens when the electrical impulses that control your heartbeat are blocked)
• for the treatment of newborn infants with congenital (acquired before birth) syphilis

Warnings and precautions

Talk to your doctor or pharmacist before you are given Cindolin.

• if you have ever had any allergic reactions to other antibiotics like pencillin or other beta-lactam antibiotics.
• if you have kidney problems (your doctor may need to adapt the dose of this medicine)
• if you have liver problems

Cindolin should not be used in tissues with poor blood flow.

If allergic symptoms occur (e.g. skin rash, itching, shortness of breath), consult a doctor immediately. If an allergic reaction occurs, your doctor will stop your treatment and, if necessary, start appropriate therapy.

As a possible cross-allergy should be considered in patients with hypersensitivity to cephalosporins and carbapenems, please tell your doctor if you have already had a previous allergic reaction to certain antibiotics (cephalosporins, carbapenems).

If you have already been diagnosed with an allergy and/or allergic asthma or hay fever, you should tell your doctor. Severe immediate allergic reactions are possible even when the drug is administered for the first time. Based on general principles, in particular in some cases, you will remain under observation for at least an hour after the medicine has been administered in case an acute allergic reaction should occur. If an allergy occurs, the doctor will take appropriate measures. Treatment with Cindolin must be stopped immediately.

When treating syphilis, a bodily reaction to the bacterial toxins may occur, which lasts up to several days (Jarisch-Herxheimer reaction, see section 4). Typical symptoms are sudden fever (sometimes with chills), pallor - followed by skin redness, headache, painful muscles and joints or tiredness. To suppress or alleviate a Jarisch-Herxheimer reaction, your doctor will start appropriate therapy.

If you experience severe, watery diarrhoea during or after treatment, which may be accompanied by fever or abdominal pain, you should contact your doctor straight away, since this may be due to a serious bowel disease (pseudomembranous enterocolitis).

Long-term and repeated use may lead to the overgrowth of non-susceptible bacteria and yeasts.

In long-term treatment, your doctor may arrange for checks on your blood count and kidney function tests. Please make sure that you attend the check-ups prescribed by the doctor.

In patients with dermatomycosis (fungal infection of the skin), allergic reactions may occur when first dosed with Cindolin because of shared antigenicity between penicillin and dermatophytes (fungi that cause skin infections).

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

Decreased elimination of povidone (one excipient included in this drug) should be considered in case of impairment of renal function. It cannot be excluded that in very rare cases to an accumulation of povidone or a local deposition and formation of granulomas may occur, which may be confused with tumors.

An effect on diagnostic laboratory procedures should also be considered (see also section 4).

Because the medicinal product contains lidocaine, Cindolin should be used with particular caution in patients with:

• kidney and/or liver disease
• myasthenia gravis (disease leading to muscle weakness)
• a lowered seizure threshold of the central nervous system (e.g. in epilepsy)
• heart disorders including conduction disorders
• slow heartbeat
• respiratory depression (breathing difficulties with slow and shallow breathing)
• poor general health condition or elderly patients

Embolic toxic reactions possibly due to vascular occlusion by large crystals of the penicillin salt may be exacerbated by the lidocaine contained in this medicinal product (Hoigné’s syndrome and Nicolau’s syndrome).

Cindolin should be avoided in patients with a disorder of the biosynthesis of the red pigment that gives blood its colour (porphyria) because of the lidocaine contained in this medicinal product.

Cindolin should be used with particular caution in patients with bleeding disorders or treatment for bleeding disorders or treatment with ‘Non-Steroidal Anti-Inflammatory Drugs’ or plasma substitutes as accidental injury of blood vessels may lead to serious bleedings.

Other medicines and Cindolin

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Benzathine benzylpenicillin may affect or be affected by other medicines.

Caution should be exercised when administering Cindolin at the same time as the following medicines:

• probenecid and sulphinpyrazone, medicines used to treat gout
• salicylates, medicines to reduce pain and to prevent blood clots
• indomethacin and phenylbutazone, medicines to reduce pain
• methotrexate, a medicine used in chemotherapy. The combination with methotrexate is not recommended.
• anticoagulants, medicines used to thin the blood

Lidocaine may affect or be affected by other medicines. In particular, tell your doctor if you are taking

any of the following:

• medicines used to treat heart disorders including irregular heartbeats such as beta blockers or calcium channel blockers
• medicines that narrow your blood vessels (vasoconstrictors, e.g. epinephrine, norepinephrine)
• other anaesthetics including local anaesthetics
• sleeping pills and medicines that reduce your level of consciousness (sedatives)
• medicines used to relax muscles (non-depolarising muscle relaxants)
• medicines that increase the risk of getting fits and seizures (e.g. tramadol, bupropion)
• medicines that decrease the risk of getting fits and seizures (e.g. diazepam)

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

There are no adequate data to support the use of benzathine benzylpenicillin and lidocaine, the pharmacologically active ingredients of Cindolin, in pregnant women. Therefore, Cindolin should be used during pregnancy only if absolutely necessary.

Breast-feeding

Benzylpenicillin and lidocaine are excreted in breast milk.

When Cindolin is used whilst breast-feeding, sensitisation and interference with the normal intestinal bacterial flora cannot be ruled out in the breast-fed infant.

The infant should be monitored for diarrhoea and mucosal yeast colonisation.

Driving and using machines

As this medicine contains lidocaine, it cannot be ruled out in individual cases that the ability to drive (actively take part in road traffic), use machines or work at heights may be impaired for a short time after the injection.

Your doctor must therefore decide in your particular case whether it is safe for you to drive (actively take part in road traffic) or use machines.

Cindolin contains povidone

Delayed excretion of povidone should be taken into consideration in patients with renal impairment. As this product contains povidone, it cannot be ruled out that frequent or prolonged use may very rarely lead to the accumulation of povidone in the reticuloendothelial system (RES), or to local deposits and the formation of foreign body granulomas which may be confused with tumors.

Cindolin contains sodium

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

3. How to use Cindolin

Cindolin is usually administered by a health practitioner. Check with your doctor or pharmacist if you are not sure about how this medicine is to be administered.

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, however not more than 2.4 Million

IU

If clinical symptoms return 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 Million IU once weekly

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

1. a) without cardiac involvement: at least 5 years, or up to 21 years of age
2. b) transient cardiac involvement: at least 10 years, or up to 21 years of age
3. c) persistent cardiac involvement: at least 10 years or up to 40 years of age; life-long prophylaxis is sometimes necessary.

Special patient groups (with kidney or liver problems or with cardiac insufficiency) The dosage and dosing interval will be determined by your doctor. If you have any questions on your dosage, please contact the doctor.

Use in children

Cindolin should not be used in children with a body weight below 3.5 kg in order to avoid exceeding the maximum dose for lidocaine.

In children less than 4 years of age, Cindolin should be used with special caution due to the content of lidocaine.

Method of administration

For intramuscular use only (the preparation may only be injected into a muscle)

Cindolin is not suitable for injecting under the skin, into blood vessels or into the spinal canal!

In case of repeated intramuscular application, the injection site must be changed.

Severe local reactions may occur during intramuscular administration, especially in young children. For this reason, other treatments such as a different penicillin formulation can be used where possible.

Important information for doctors/healthcare professionals regarding the method of administration is provided at the end of this package leaflet.

If more Cindolin is used than you should

At extremely high doses, penicillins can cause neuromuscular excitability or epileptiform seizures. If overdose is suspected, tell a doctor immediately for advice.

An overdose of lidocaine mainly affects your central nervous system. If you begin to experience dizziness or lightheadedness, numbness of the tongue, a ringing in the ear, vomiting or shivering, you must tell the person giving you the injection immediately. Your doctor will know how to manage these symptoms and give you any necessary treatment.

Important information for doctors/healthcare professionals regarding the symptoms of overdose/misuse is provided at the end of this package leaflet.

If you forget to use Cindolin

If you think that you have not been given a dose, talk to your doctor immediately.

If you stop using Cindolin

You should not stop your treatment with Cindolin without checking with your doctor first. Or else there is a risk that your disease may not yet have been fully cured and that you might have a relapse.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Important side effects to look out for:

Severe allergic reaction (may affect up to 1 in 10,000 people)

If you have a severe allergic reaction (anaphylaxis), tell a doctor straight away.

The signs may include: shock with circulatory failure, sweating and impaired consciousness (life-threatening; see also section 2 under “Warnings and precautions”)

Severe skin rashes

If you get a severe skin rash, tell a doctor straight away:

The signs may include:

• Very rare (may affect up to 1 in 10,000 people): blistering, usually with involvement of mucous membranes (Stevens-Johnson syndrome, toxic epidermal necrolysis)

• Frequency not known: increased numbers of certain blood cells as a sign of hypersensitivity

  (eosinophilia), wheals that cause severe itching (urticaria), swelling of the skin and mucous

  membranes, especially in the face, mouth, throat and voice box (angioneurotic oedema), inflammation of the blood vessels with bleeding of the skin and mucous membranes (leucocytoclastic vasculitis, Henoch-Schönlein purpura), tender skin nodules (erythema nodosum)

Any immediate-type reaction with wheals that cause severe itching (urticaria) must always be considered a serious sign and strictly mandates discontinuation of treatment.

Benzylpenicillin may cause the following side effects:

Common (may affect up to 1 in 10 people)

• hypersensitivity reactions (The frequency of many individual symptoms of allergic reactions cannot be estimated with sufficient accuracy based on the available data.)
• rash (morbilliform or scarlatiniform)
• induration at the injection site, fever

• Change in certain tests and investigations, such as:

  • positive direct Coombs’ test.

  • false-positive tests to determine protein in the urine, using precipitation techniques (Folin-

    Ciocalteu-Lowry method, biuret method).

  • false-positive tests to determine protein in the urine (ninhydrin method).

  • simulation of pseudobisalbuminaemia (transient changes of properties of blood proteins

    (albumin)) when using electrophoresis methods to determine albumin.

  • false-positive non-enzymatic tests to detect glucose in the urine and urobilinogen.

  • increased levels when determining 17-ketosteroids in urine (using the Zimmermann reaction)

    (see section 2).

Uncommon (may affect up to 1 in 100 people)

• inflammation of the tongue and oral mucosa, black hairy tongue, feeling sick (nausea), being sick

  (vomiting), diarrhoea

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

• severe, watery diarrhoea during or after treatment, which may be accompanied by fever or abdominal pain, due to a serious bowel disease (pseudomembranous colitis) (see also section 2 under “Warnings and precautions”).
• serum sickness (symptoms include, but are not limited to, fever, joint swelling and rash)
• kidney disease (nephropathy), kidney inflammation (interstitial nephritis)

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

• certain blood disorders (so-called haemolytic anaemia, leukopenia, thrombocytopenia, agranulocytosis)
• liver cell injury, stoppage of the flow of bile. These reactions occurred in association with shock, rash, exfoliative dermatitis, fever and/or increased numbers of certain blood cells as a sign of hypersensitivity (eosinophilia) or serum sickness syndrome.

Not known (frequency cannot be estimated from the 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 the first dose) and is characterised by fever, rigors, systemic and focal symptoms)

• blockage of blood vessels (arteries)
• swelling of the voice box, spasmodic narrowing of the bronchi with shortness of breath, allergic lung disease (pulmonary eosinophilia)

• Embolic toxic reactions possibly due to vascular occlusion by large crystals of the penicillin salt

  (Hoigné’s syndrome and Nicolau’s syndrome), pain at the injection site, which may occur even with appropriate injection technique. The local numbing agent contained in this medicine provides initial pain relief. Once the pain relieving effect wears off, the pain may persist for some time.

Other side effects/further information

Nervous system side effects, which are possible with high-dose penicillin therapy, do not occur because of the low blood levels attained with Cindolin.

Lidocaine may cause the following side effects:

Because of the low lidocaine content and the low frequency of use of Cindolin, the risk of dose-related systemic adverse reactions to lidocaine is low when this product is used as intended. Despite the low lidocaine (pain relieving active substance) content, you should also watch out for lidocaine side effects. Reactions affecting the body as a whole may occur, e.g. after accidental injection into a vein.

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

• allergic reactions

Not known (frequency cannot be estimated from the available data)

• dizziness, light-headedness, convulsions (seizures), pins and needles around the mouth, numbness of the tongue, feeling drowsy
• abnormally slow heartbeat, heart rhythm disorders, cessation of normal circulation of blood due to failure of the heart, cardiac arrest, mild blood pressure increase, low blood pressure, circulatory shock
• respiratory depression
• nausea, vomiting
• skin rash, oedema

This medicine contains phospholipids from the soya bean ((3-sn-phosphatidyl)choline), caution is warranted on the risk of allergic reactions.

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.

Important information for doctors/healthcare professionals regarding possible serious side effects in case of accidental injection into blood vessels is provided at the end of this package leaflet.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

You can also report side effects directly via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Cindolin

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 vial label and on the carton after “EXP”. The expiry date refers to the last day of that month.

Store in the original package in order to protect from light.

The reconstituted suspension for injection should be prepared fresh immediately before use.

Do not throw away any medicines via wastewater <or household waste>. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Cindolin contains

• The active substances are benzathine benzylpenicillin and lidocaine hydrochloride monohydrate.

  1 vial of powder contains 916.7 mg benzathine benzylpenicillin (as tetrahydrate), equivalent to 1,200,000 IU benzathine benzylpenicillin..

  1 ampoule of 5 ml solution contains 25 mg lidocaine hydrochloride monohydrate.

• The other ingredients in the vial of powder are:

  Povidone K17, soya bean lecithin, polysorbate 80, sodium citrate (anhydrous), citric acid, mannitol (E421), simethicone.

• The other ingredients in the ampoule of solution are:

  sodium hydroxide, water for injections.

What Cindolin looks like and contents of the pack

Cindolin consists of one vial containing a white to cream-coloured powder and one ampoule containing a clear, colourless solution.

After reconstitution the ready-to-use medicine is a milky-white homogeneous suspension for injection.

Cindolin is available in packs containing 1 vial and 1 ampoule and in multipacks comprising 5 cartons with 1 vial and 1 ampoule, each.

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 Member States of the EEA under the following names:

Austria: Tarlidocin

France: Tarlidocin

Germany: Tarlidocin

Italy: Tarlidocin

Netherlands: Tarlidocin

United Kingdom:Cindolin

This leaflet was last revised in 11/2020.

The following information is intended for healthcare professionals only:

Method of administration

The preparation is strictly for intramuscular injection. The injection must not be administered into tissue with reduced perfusion.

Reconstitution of the suspension for intramuscular injection

The powder of one vial should be reconstituted with the solution in the ampoule.

To open the glass ampoule, the top should be snapped off by defined breaking at the ampoule neck.

Use a sterile syringe with a needle to draw up the complete solution in the ampoule.

To reconstitute the suspension for injection, the syringe needle should be introduced through the rubber stopper of the vial so that the end of the needle is solely in the upper part of the vial.

Then the solution should be completely and slowly injected into the vial and the vial should be swirled. Vigorous shaking should be avoided.

The procedure described above helps avoid solution squirting out and foaming.

The ready-to-use medicinal product is a milky-white, homogeneous suspension for injection. After reconstitution with the solution provided in this pack, the volume of the ready-to-use suspension for injection is 6 ml.

Administration of 1.2 Million IU (equivalent to 1 vial):

The content of a vial should be completely drawn up and then administered.

Administration of lower doses, e.g. 600,000 IU (equivalent to ½ a vial):

The content of a vial should be completely drawn up. Half of the content should be discarded immediately, and the second half of the content should be administered.

The suspension for injection is intended for single use only. The product must be used immediately after opening the ampoule and reconstituting the suspension for injection.

Any remaining medicinal product after dispensing the single dose should be discarded.

Injection

Using a long, large gauge needle (cannula diameter 0.90 mm), the injection of Cindolin must be made by deep intramuscular injection into the upper outer quadrant of the gluteal musculature in the direction of the iliac crest or by von Hochstetter’s technique. The needle should be inserted as perpendicularly to the skin surface as possible, and the injection should be made as far away from larger vessels as possible. Always aspirate before injecting. If blood is aspirated or if the patient experiences pain during the injection, the injection must be stopped.

In children, the mid-lateral thigh muscles (m. 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.

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

The injection should be made as slowly as possible and by applying only little 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).

During long-term treatment with depot penicillins (e.g. for the treatment of syphilis), repeated injections into a closely confined area in muscle tissue may lead to tissue injury and ingrowth of blood vessels, thus increasing the likelihood of injected material entering the circulation with each further injection − either by direct injection into a blood vessel or by squeezing material into the circulation as a result of the injection pressure, or even by spreading the depot by “rubbing”. During long-term treatment, it is therefore recommended to administer each injection as far away as possible from the site of the preceding injection.

Note

Because of the possible adverse reactions (Nicolau’s syndrome or Hoigné’s syndrome in association with the effect of lidocaine), it is imperative to rule out an intravascular needle position by doing an aspiration test with an empty injection syringe.

If blood is aspirated or if the patient experiences pain during the injection, the injection must be stopped.

Cindolin is not suitable for subcutaneous, intravenous or intralumbar injection.

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

Symptoms of overdose/misuse

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

Lidocaine intoxication following inappropriate administration of too much lidocaine occurs in two phases. Initially patients experience excitatory central and cardiac symptoms: agitation, unrest, dizziness, disturbances of hearing and vision, perioral tingling, slurred speech, nausea, vomiting, shivering and muscular twitching which may be signs of an imminent seizure. Cardiovascular symptoms may include arrhythmia, tachycardia, hypertension and flushing. As intoxication progresses, patients develop depression of central and cardiac functions resulting in coma, respiratory and circulatory arrest. A frequent prodrome is hypotension. 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

Benzylpenicillin is haemodialysable.

At the first signs of a lidocaine overdose, the administration of Cindolin must be stopped immediately. Administration of oxygen is recommended. Additional treatment should be symptomatic in response to the signs of intoxication: A seizure is an indication for intravenous administration of diazepam, and respiratory and circulatory arrest should be managed with the usual procedures of cardiopulmonary resuscitation.

Central analeptic agents are contraindicated in intoxication with local anaesthetics.