Pentamidine Isetionate Tillomed 300 mg powder for solution for injection/infusion – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Pentamidine isetionate Tillomed 300 mg powder for solution for injection/infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains 300 mg pentamidine isetionate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for injection/infusion

white to off-white lyophilized powder/cake.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Pentamidine isetionate is indicated in adults and children for

• Prophylaxis and therapy of Pneumocystis jirovecii (formerly known as Pneumocystis carinii) pneumonia.
• Treatment of visceral and cutaneous Leishmaniasis.
• Treatment of first-stage of human African trypanosomiasis due to Trypanosoma brucei gambiense.

Consideration should be given to official guidance on the appropriate use of antiprotozoal agents.

4.2 Posology and method of administration

Posology

The following dosage recommendations apply to adults, adolescents, children and infants:

Pneumocystis jirovecii (formerly known as Pneumocystis carinii) pneumonia Prophylaxis

Inhalation of pentamidine is recommended for the prophylaxis of Pneumocystis jirovecii pneumonia (see below "Method of administration").

The adult dosage for inhalation is 150 mg pentamidine isetionate every two weeks or one dose of 300 mg once a month.

Therapy

For the therapy of Pneumocystis jirovecii pneumonia, intravenous infusion of the medicinal product is recommended (see below "Method of administration").

4 mg of pentamidine isetionate per kg body weight once daily is preferably administered by slow intravenous infusion over 60 minutes. The therapy duration of 14 days is generally sufficient. In some severe cases, prolonging the therapy may be necessary.

The total duration of therapy should not exceed 21 days.

Leishmaniasis

Visceral: 3-4 mg pentamidine isetionate per kg body weight is most conveniently administered by intramuscular injection every other day. The number of applications should not exceed 10. However, it is also possible to administer a second treatment cycle if necessary.

Cutaneous: 3-4 mg of pentamidine isetionate per kg of body weight every other day for 3-4 doses by intramuscular injection or intravenous infusion.

Human African Trypanosomiasis

4 mg of pentamidine isetionate per kg of body weight once a day or every other day. Pentamidine is injected intramuscularly or infused intravenously up to a total of 7-10 applications (also see under "Method of administration").

Special populations

Renal impairment:

In case of severely impaired renal function (creatinine clearance <10 ml / min) a dose adjustment is required:

• For life-threatening Pneumocystis jirovecii pneumonia, 4 mg pentamidine isetionate per kg of body weight should be given once daily for 7-10 days. Thereafter, the dose is given every 2 days to a total of at least 14 doses.
• In less severe cases of Pneumocystis jirovecii pneumonia, 4 mg pentamidine isetionate per kg body weight should be given every 2 days.
• For trypanosomiasis and leishmaniasis, the dosing interval should not be less than 48 hours.

In mild cases of renal impairment, at least 36 hours should have elapsed between doses of the product.

Hepatic impairment:

No specific dosage recommendations. In patients with a decrease in hepatic function, the benefits of continuation of therapy should outweigh the potential risk.

Elderly:

No specific dosage recommendations.

Paediatric population:

For infants, children and adolescents, the dosage recommendations given above apply.

Method of administration

Administration by intramuscular or intravenous or inhalation use.

Depending on the indication, the medicinal product is injected intramuscularly after appropriate preparation, infused intravenously or inhaled orally (nasal masks are not suitable).

The infusion/injection should be done with extra caution and with the patient in a reclining position (see also section 4.4)

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

Notes for inhalation:

The optimal particle size for alveolar deposition is between 1 and 5 microns.

The freshly prepared solution should be administered by inhalation using a suitable nebuliser such as a Respirgard II (trademark of Marquest Medical Products Inc.), Modified Acorn system 22 (trademark of Medic-Aid) or an equivalent device with either a compressor or piped oxygen at a flow rate of 6 to 10 Litres/Minute.

The nebuliser should be used in a vacated, well-ventilated room. Only staff wearing adequate protective clothing (mask, goggles, gloves) should be in the room when nebulisers are being used.

1. a) This medicinal product should be reconstituted in a fume cupboard.
2. b) A suitable well fitted one-way system should be employed such that the nebuliser stores the aerosolised drug during exhalations and disperses exhaled pentamidine into a reservoir. A filter should be fitted to the exhaust line to reduce atmospheric pollution. It is advisable to use a suitable exhaust tube which vents directly through a window to the external atmosphere. Care should be taken to ensure that passers-by will not be exposed to the exhaust.
3. c) All bystanders including medical personnel, women of child-bearing potential, pregnant women, children, and people with a history of asthma, should avoid exposure to atmospheric pentamidine resulting from nebuliser usage.

Dosage equivalence: 4 mg of pentamidine isetionate contains 2.3 mg pentamidine base; 1 mg of pentamidine base is equivalent to 1.74 mg pentamidine isetionate.

Displacement value: 300 mg of pentamidine isetionate displace approximately 0.15 ml of water.

5-10 minutes prior to inhalation therapy, a bronchodilator should be used as a metered dose inhaler. Bronchospasm has been reported to occur following the use of nebuliser (see section 4.8). This has been particularly noted in patients who have a history of smoking or asthma. This can be controlled by prior use of bronchodilators.

Since the pathogens in the Pneumocystis jirovecii pneumonia are located in the air sacs (alveoli), it is important that the nebulised pentamidine particles also reach there. This is only possible if the particle size is between 1 and 5 microns. Therefore, only suitable nebulisers may be used for the pentamidine inhalation therapy.

Only clear solutions practically free from particles should be used.

In order to minimise the indoor air contamination when using pentamidine as an aerosol, the corresponding functional rooms should be frequently and extensively ventilated and the inhaler systems should be switched off during the inhalation pauses.

4.3 Contraindications

• Hypersensitivity to the active substance.

4.4 Special warnings and precautions for use

Since there may be a sudden and severe fall in blood pressure even after an injection of pentamidine, the patient should be reclining when administered the medicinal product. Continuous monitoring of blood pressure should be ensured during and after the infusion / injection.

Pentamidine should be used with caution in patients with hypertension, hypotension, hyper-glycemia, hypoglycemia, hypocalcemia, leukopenia, thrombocytopenia or anemia, and hepatic or renal impairment. In these patients, a particularly close monitoring of the corresponding laboratory parameters is indicated. Fatal cases of severe hypotension, hypoglycaemia, acute pancreatitis and cardiac arrhythmias have been reported with pentamidine therapy following intravenous and intramuscular administration. Before administration, blood pressure should be checked with the patient in a supine position. Blood pressure should be monitored during administration of pentamidine and regularly until the end of therapy. Inhalation therapy should also be performed with care and under medical supervision. Patients should be monitored for the development of symptoms of a severe adverse reaction.

Bronchospasm has been reported when inhaled with a nebuliser (see section 4.8), especially in patients with a history of asthma or in case of smokers. Pre-administration of an inhaled bronchodilator reduces coughing and bronchospasm and improves aerosol deposition.

Pentamidine isetionate may prolong the QT interval. Cardiac arrhythmias, such as Torsades de pointes, which indicate a QT prolongation, have been reported occasionally during pentamidine isetionate therapy. Therefore, pentamidine isetionate should be used with caution in patients at an increased risk of developing cardiac arrhythmias, prolonged QT syndrome, cardiac disease (e.g, coronary heart disease, cardiac failure), and known ventricular arrhythmias, with bradycardia (<50 bpm) or during concomitant administration of pentamidine isethionate with QT prolonging agents (see section 4.5), patients with untreated hypokalaemia and / or hypomagnesemia Monitoring of QTc interval is necessary in patients with known or suspect cardiac disease or taking concomitant QT-prolonging medications. Special care should be taken when QTc interval exceeds 500 ms during therapy. Continuous monitoring of cardiac function should be considered in these cases. If the QTc interval exceeds 550 ms, alternative therapy should be considered. Other precautions

The following examinations should be carried out regularly:

• Blood Urea nitrogen and serum creatinine daily throughout the therapy.
• Complete blood count on each day of therapy.
• Fasting blood sugar on each therapy day and at regular intervals after the end of the therapy. In some cases, hyperglycemia and diabetes mellitus have occurred months after the end of therapy.
• Liver function tests, in particular bilirubin, alkaline phosphatase, aspartate aminotransferase (AST / SGOT) and alanine aminotransferase (ALT / SGPT). For baseline values and in case of only minor changes, a weekly determination is sufficient. If the pre therapy values or values during therapy are elevated, the tests should also be performed once a week, unless the patient is treated with other hepatotoxic preparations, in which case it should be checked approximately every 3-5 days.
• Serum Calcium once a week, Serum magnesium twice a week.
• Urinalysis and determination of serum electrolytes daily during the period of therapy.
• Electrocardiograms at regular intervals.

The benefit of pentamidine inhalation therapy in patients at high risk for pneumothorax should be weighed against the clinical consequences of such manifestation.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent use of dideoxyinosine is associated with an increased risk of pancreatitis. Coadministration of foscarnet may cause severe renal impairment and hypocalcemia. Systemic therapy with pentamidine and amphotericin B is associated with severe renal impairment. Nephrotoxic interaction has not been described with inhalation therapy of pentamidine.

Caution is advised with the simultaneous administration of preparations that prolong the QT interval, such as phenothiazine, tricyclic antidepressants, terfenadine, astemizole, intravenous erythromycin, halofantrine and quinolones (see also section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

So far, there are none or very limited experience with the use of pentamidine in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). A miscarriage was reported after inhalation of pentamidine for prophylaxis in the first trimester of pregnancy. Pentamidine isetionate should not be used during pregnancy unless therapy with pentamidine is required due to the woman's clinical condition. Breast-feeding

It is not known if pentamidine / metabolites are excreted in breast milk. Breastfeeding should be discontinued during pentamidine therapy.

Fertility

There are no clinical or animal data on the effects of pentamidine on fertility.

4.7 Effects on ability to drive and use machines

There are no reports of impaired ability to drive and use machines. Considering the possible side effects (e.g. dizziness, syncope and others), caution is advised.

4.8 Undesirable effects

The frequency of side-effects is based on the following categories:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); Not known (cannot be estimated from the available data).

Adverse reactions in parenteral administration:

Adverse reactions of inhalation treatment:

Note:

As severe, occasional life-threatening adverse reaction (see above) cannot be ruled out with inhalation therapy of pentamidine, patients should be closely monitored for the development of severe adverse reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Cardiac arrhythmias, including Torsades de Pointes, have been reported after overdose with pentamidine isetionate.

Treatment is symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiprotozoals, Agents against Leishmaniasis and Trypanosomiasis, Other agents against leishmaniasis and trypanosomiasis ATC code: P01CX01.

Mechanism of action

The antiprotozoonotic pentamidine is an aromatic diamidine which exerts its effects through interactions with DNA, interfering with folic acid metabolism and inhibiting RNA and protein synthesis.

Mechanism of resistance

Pentamidine resistance in Leishmania spp. is multifactorial, being mediated by several energy-dependent molecular pumps that alter transport of pentamidine into and out of the parasite. Modification of three different transporter proteins responsible for trafficking of pentamidine can mediate resistance, including an ATP-binding cassette (ABC) transporter, pentamidine resistance protein 1 (PRP1), and a P-glycoprotein homolog that causes efflux of pentamidine from the parasite. Pentamidine-susceptible L. infantum amastigotes can be rendered pentamidine-resistant by transfecting them with PRP1 genes. The calcium channel blocker verapamil (at therapeutic concentrations) can reverse the effect of the PRP1 gene, restoring in vitro pentamidine susceptibility. In T. brucei gambiense, mutations in an aquaporin gene (aquaglyceroporin TbAQP2) have been identified that confer cross-resistance to both pentamidine and melaminophenyl arsenic drugs (melarsoprol/cymelarsan). Pentamidine binds to wild-type aquaglyceroporin in nanomolar concentrations and inactivates the porin channel activity that helps maintain osmotic balance and bidirectional flux of solutes. The mutations inhibit binding of pentamidine to this channel protein.

5.2 Pharmacokinetic properties

After intravenous infusion of 4 mg pentamidine isetionate per kg body weight over 2 hours, maximum plasma levels of approximately 0.5 μg / ml are achieved; after intramuscular injection of the same dose, the maximum concentration in plasma is approximately 0.2 μg / ml.

* The mean with standard deviation is indicated.

In addition, the following pharmacokinetic parameters were determined:

* The mean with standard deviation is indicated.

When administered by the use of a nebuliser, human kinetic studies revealed significant differences when compared to parenteral administration. Aerosol administration resulted in a 10-fold increase in bronchial alveolar lavage (BAL) supernatant fluid and an 80-fold increase in BAL sediment concentrations in comparison with those seen with equivalent intravenous doses.

Limited data suggests that the half-life of pentamidine in BAL fluid is greater than 10 to 14 days. Peak plasma concentrations after inhalation therapy were found to be approximately 10% of those observed with equivalent intramuscular doses and less than 5% of those observed following intravenous administration. This suggests that systemic effects by the inhalation route are less likely.

Long term pulmonary parenchymal effects of aerosolised pentamidine are not known. Lung volume and alveolar capillary diffusion, however, have not been shown to be affected by high doses of pentamidine administered by inhalation to AIDS patients.

5.3 Preclinical safety data

In the various toxicological tests, toxicity symptoms of hypotension and CNS depression were observed in all species. Hypotension was most pronounced at intravenous bolus injection. With longer application time, an adaptation occurs. The symptoms become less severe during the course of administration and occur less frequently.

Nephrotoxic effects were mainly observed in toxicity studies in dogs and rats, but no effect on the morphological structure and weight of the kidneys was detected. There was also evidence in the rat studies that the liver was damaged. Again, the morphology of the liver was not changed; the liver weight was increased, in dogs as well. After 3 weeks of recovery, the pathological LFTs of the rats returned to normal. The local tolerance in these two species was very poor. However, in case of rabbits, there were no indications of relevant local reactions during intravenous and intraarterial administration.

Rabbit teratology revealed a low fetal toxicity, which could be partly explained by the maternal toxic effect.

Studies on embryotoxicity in a second animal species as well as animal studies on fertility and potential harm during use during the gestation period and lactation were not performed.

There is no human experience of the safety of use during pregnancy and lactation. It is not known whether the active substance passes into breast milk.

Pentamidine isetionate can in principle interact with the DNA. However, the substance was unremarkable in several in vitro and in vivo mutagenicity tests. Long-term carcinogenicity studies were not performed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6

6.3 Shelf life

3 years

After first opening:

The medicinal product must be used immediately.

After reconstitution/dilution:

The chemical and physical in-use stability of the solution diluted in glucose 50 mg/ml (5 %) solution or sodium chloride 9 mg/ml (0.9 %) solution has been demonstrated for 24 hours at a temperature (20-25 °C).

From a microbiological point of view, the medicinal product should be used immediately, if not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at (2 to 8°C) unless reconstitution/ dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions. For storage conditions after first opening, after reconstitution and dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

20 ml Type-I, clear glass vial stoppered with 20 mm dark grey rubber stopper and sealed with flip-off seal.

Pack sizes: 1 and 5 vials

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Preparation of the solution for injection/infusion and nebuliser solution

The powder should be reconstituted in a fume cupboard. For reconstitution, 5 mL of sterile water for injections should be added aseptically. After reconstitution 1 mL solution contains 60 mg of pentamidine isetionate.

The solution for injection/infusion should be inspected visually for particulate matter and discolouration prior to administration. After reconstitution the medicine is a clear, colourless solution free from visible particles. The vial should be discarded, if visible particles are observed.

For intravenous infusion, the required volume up to 5 mL (300 mg) of pentamidine isetionate should be withdrawn and transferred into an intravenous bag containing 50-200 ml of Glucose 50 mg/ml (5 %) solution for injection or sodium chloride 9 mg/ml (0.9 %) solution for injection. The diluted solution should be mixed by gentle inversion. Other solutions for infusions should not be used.

The medicinal product is for single use only. Any unused portion left in the vial should be discarded.

For inhalation, if necessary, the required dose may be diluted further with water for injections prior to administration to the nebuliser.

Disposal instructions

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

7 MARKETING AUTHORISATION HOLDER

Tillomed Laboratories Limited

220 Butterfield, Great Marlings,

Luton, LU2 8DL,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 11311/0675

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

19/07/2022

10 DATE OF REVISION OF THE TEXT

27/06/2023