4.1. Therapeutic indications

Paroxysmal nocturnal haemoglobinuria

FABHALTA is indicated as monotherapy in the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH) who have haemolytic anaemia.

Complement 3 glomerulopathy

FABHALTA is indicated for the treatment of adult patients with complement 3 glomerulopathy (C3G) in combination with a renin-angiotensin system (RAS) inhibitor, or in patients who are RAS-inhibitor intolerant, or for whom a RAS inhibitor is contraindicated (see section 5.1).

4.2. Posology and method of administration

Posology

The recommended dose is 200 mg taken orally twice daily.

Healthcare professionals should advise patients about the importance of adherence to the dosing schedule. In patients with PNH, adherence is important to minimise the risk of haemolysis (see section 4.4).

If a dose or doses are missed, the patient should be advised to take one dose as soon as possible (even if it is shortly before the next scheduled dose) and then to resume the regular dosing schedule. Patients with PNH who have missed several consecutive doses should be monitored for potential signs and symptoms of haemolysis.

PNH is a disease that requires chronic treatment. Discontinuation of this medicinal product is not recommended unless clinically indicated (see section 4.4).

Patients with PNH switching from anti-C5 (eculizumab, ravulizumab) or other PNH therapies to iptacopan

To reduce the potential risk of haemolysis with abrupt treatment discontinuation:

• For patients switching from eculizumab, iptacopan should be initiated no later than 1 week after the last dose of eculizumab.

• For patients switching from ravulizumab, iptacopan should be initiated no later than 6 weeks after the last dose of ravulizumab.

Switches from complement inhibitors other than eculizumab and ravulizumab have not been studied.

Patients with C3G after kidney transplantation (recurrent C3G)

Diagnosis of recurrent C3G should be made based on histological C3 deposition in the glomeruli of the transplanted kidney. C3 deposition may be detected in a routine post-transplantation biopsy; otherwise, a biopsy should be performed when clinical signs indicate recurrent C3G. As done in study X2202 (see section 5.1), treatment with iptacopan can be started before the onset of clinical signs such as estimated glomerular filtration rate (eGFR) decrease or urine protein-to-creatinine ratio (UPCR) increase. There is limited experience with the use of iptacopan in patients with recurrent C3G after transplantation in clinical studies (see section 5.1).

Special populations

Elderly

No dose adjustment is required for patients 65 years of age and older (see section 5.2).

Renal impairment

No dose adjustment is required in patients with mild (eGFR between 60 and <90 ml/min) or moderate (eGFR between 30 and <60 ml/min) renal impairment. No data are currently available in patients with severe renal impairment or on dialysis and no dose recommendations can be given (see section 5.2).

Hepatic impairment

The use of iptacopan is not recommended in patients with severe hepatic impairment (Child-Pugh class C). No dose adjustment is required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of iptacopan in children aged below 18 years have not been established. No data are available.

Method of administration

For oral use.

This medicinal product may be taken with or without food (see section 5.2).

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Patients who are not currently vaccinated against Neisseria meningitidis and Streptococcus pneumoniae, unless the risk of delaying treatment outweighs the risk of developing an infection from these encapsulated bacteria (see section 4.4).

• Patients with unresolved infection caused by encapsulated bacteria, including Neisseria meningitidis, Streptococcus pneumoniae or Haemophilus influenzae type B, at treatment initiation.

4.4. Special warnings and precautions for use

Serious infections caused by encapsulated bacteria

The use of complement inhibitors, such as iptacopan, may predispose individuals to serious, life-threatening or fatal infections caused by encapsulated bacteria. To reduce the risk of infection, all patients must be vaccinated against encapsulated bacteria, including Neisseria meningitidis and Streptococcus pneumoniae. It is recommended to vaccinate patients against Haemophilus influenzae type B if vaccine is available. Healthcare professionals should refer to local vaccination guideline recommendations.

Vaccines should be administered at least 2 weeks prior to administration of the first dose of iptacopan. If treatment must be initiated prior to vaccination, patients should be vaccinated as soon as possible and provided with antibacterial prophylaxis until 2 weeks after vaccine administration.

If necessary, patients may be revaccinated in accordance with local vaccination guideline recommendations.

Vaccination reduces, but does not eliminate, the risk of serious infection. Serious infection may rapidly become life-threatening or fatal if not recognised and treated early. Patients should be informed of and monitored for early signs and symptoms of serious infection. Patients should be immediately evaluated and treated if infection is suspected. The use of iptacopan during treatment of serious infection may be considered following an assessment of the risks and benefits (see section 4.8).

PNH laboratory monitoring

Patients with PNH receiving iptacopan should be monitored regularly for signs and symptoms of haemolysis, including measuring lactate dehydrogenase (LDH) levels.

Monitoring of PNH manifestations after treatment discontinuation

If treatment must be discontinued, patients with PNH should be closely monitored for signs and symptoms of haemolysis for at least 2 weeks after the last dose. These signs and symptoms include, but are not limited to, elevated LDH levels along with sudden decrease in haemoglobin or PNH clone size, fatigue, haemoglobinuria, abdominal pain, dyspnoea, dysphagia, erectile dysfunction, or major adverse vascular events (MAVEs), including venous or arterial thrombosis. If treatment discontinuation is necessary, alternative therapy should be considered.

If haemolysis occurs after discontinuation of iptacopan, restarting treatment should be considered.

Co-administration with other medicinal products

Concomitant use of iptacopan with strong inducers of CYP2C8, UGT1A1, PgP, BCRP and OATP1B1/3 has not been studied clinically; therefore, concomitant use is not recommended due to the potential for reduced efficacy of iptacopan (see section 4.5). If an alternative concomitant medicinal product cannot be identified, patients with PNH should be monitored for potential signs and symptoms of haemolysis.

Treatment of patients with C3G

Patients with C3G treated with immunosuppressant medicinal products may show modest proteinuria reduction with iptacopan, which is likely linked to a more treatment-resistant nature of C3G in these patients.

There is no experience with the use of iptacopan in patients with C3G in native kidney who have proteinuria below 1 g/g at treatment initiation.

Educational materials

All physicians who intend to prescribe FABHALTA must ensure they have received and are familiar with the physician educational materials. Physicians must explain and discuss the benefits and risks of FABHALTA therapy with the patient and provide them with the patient information pack. The patient should be instructed to seek prompt medical care if they experience any sign or symptom of serious infection or serious haemolysis (patients with PNH) following treatment discontinuation.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on iptacopan

Strong inducers of CYP2C8, UGT1A1, PgP, BCRP and OATP1B1/3

Although concomitant administration of iptacopan with strong inducers of CYP2C8, UGT1A1, PgP, BCRP and OATP1B1/3, such as rifampicin, has not been studied clinically, concomitant use with iptacopan is not recommended due to the potential for reduced efficacy of iptacopan (see section 4.4).

Effects of iptacopan on other medicinal products

CYP3A4 substrates

In vitro data showed iptacopan has potential for induction of CYP3A4 and may decrease the exposure of sensitive CYP3A4 substrates. The concomitant use of iptacopan and sensitive CYP3A4 substrates has not been studied clinically. Caution should be exercised if co-administration of iptacopan with sensitive CYP3A4 substrates is required, especially for those with a narrow therapeutic index (e.g. carbamazepine, ciclosporin, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).

CYP2C8 substrates

In vitro data showed iptacopan has potential for time-dependent inhibition of CYP2C8 and may increase the exposure of sensitive CYP2C8 substrates, such as repaglinide, dasabuvir or paclitaxel. The concomitant use of iptacopan and sensitive CYP2C8 substrates has not been studied clinically. Caution should be exercised if co-administration of iptacopan with sensitive CYP2C8 substrates is required.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of iptacopan in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at exposures between 2- and 8-fold the human exposure at the maximum recommended human dose (MRHD) (see section 5.3).

PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages and increased maternal mortality, as well as adverse foetal outcomes, including foetal death and premature delivery.

C3G in pregnancy may be associated with adverse maternal outcomes, in particular pre-eclampsia and miscarriage, as well as adverse foetal outcomes including prematurity and low birth weight.

The use of iptacopan in pregnant women or women planning to become pregnant may only be considered following a careful assessment of the risk and benefits, if necessary.

Breast-feeding

It is unknown whether iptacopan is excreted in human milk. There are no data on the effects of iptacopan on the breast-fed newborn/infant or on milk production.

A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from FABHALTA therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of iptacopan on human fertility. Available non-clinical data do not suggest an effect of iptacopan treatment on fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

FABHALTA has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in adult patients with PNH were upper respiratory tract infection (18.9%), headache (18.3%) and diarrhoea (11.0%). The most commonly reported serious adverse reaction was urinary tract infection (1.2%).

The most commonly reported adverse reaction in adult patients with C3G was upper respiratory tract infection (12.9%). The most commonly reported serious adverse reaction was pneumococcal infection (1%).

Tabulated list of adverse reactions

Table 1 shows the adverse reactions observed in the clinical studies with iptacopan in patients with PNH and C3G. Adverse reactions are listed by MedDRA system organ class (SOC) and frequency, using the following convention: 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) or very rare (<1/10 000).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions

System Organ Class

Adverse reaction

Frequency category

PNH

C3G

Infections and infestations

Upper respiratory tract infection1

Very common

Very common

Urinary tract infection2

Common

Bronchitis3

Common

Pneumococcal infection4

Common

Pneumonia bacterial

Uncommon

Blood and lymphatic system disorders

Platelet count decreased

Common

Nervous system disorders

Headache5

Very common

Dizziness

Common

Gastrointestinal disorders

Diarrhoea

Very common

Abdominal pain6

Common

Nausea

Common

Skin and subcutaneous tissue disorders

Urticaria

Uncommon

Musculoskeletal and connective tissue disorders

Arthralgia

Common

1 Upper respiratory tract infection includes preferred terms influenza, nasopharyngitis, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, and viral upper respiratory tract infection..

2 Urinary tract infection includes preferred terms urinary tract infection and cystitis escherichia.

3 Bronchitis includes preferred terms bronchitis, bronchitis haemophilus and bronchitis bacterial.

4 Pneumococcal infection includes preferred terms pneumonia pneumococcal and pneumococcal sepsis.

5 Headache includes preferred terms headache and head discomfort.

6 Abdominal pain includes preferred terms abdominal pain, abdominal pain upper, abdominal tenderness and abdominal discomfort.

Description of selected adverse reactions

Infections

In PNH clinical studies 1/164 (0.6%) patients with PNH reported serious bacterial pneumonia while receiving treatment with iptacopan; the patient had been vaccinated against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type B and recovered following treatment with antibiotics while continuing treatment with iptacopan.

In C3G completed clinical studies, 1 patient with C3G reported serious pneumococcal infection with pneumonia and sepsis while receiving treatment with iptacopan; the patient had been vaccinated against Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type B and recovered following treatment with antibiotics. Iptacopan treatment was interrupted and restarted after recovery.

Platelet count decreased in patients with PNH

Decrease in platelet count events was reported in 12/164 (7%) patients with PNH. Of these, 5 patients had events of mild severity, 5 had moderate events and 2 had severe events. Patients with severe events had concurrent anti-platelet antibodies or idiopathic bone marrow aplasia with pre-existing thrombocytopenia. The events started within the first 2 months of iptacopan treatment in 7/12 patients, and after a longer exposure (111 to 951 days) in 5/12 patients. At the cut-off date, 7 (58%) patients had recovered or events were resolving and iptacopan treatment was continued throughout in all patients.

Blood cholesterol and blood pressure increases in patients with PNH

In patients treated with iptacopan 200 mg twice a day in PNH clinical studies, mean increases from baseline of approximately 0.7 mmol/l were seen at month 6 for total cholesterol and LDL-cholesterol. The mean values remained within the normal ranges. Increases in blood pressure, particularly diastolic blood pressure (DBP), were observed (mean increase 4.7 mmHg at month 6). The mean DBP did not exceed 80 mmHg. Total cholesterol, LDL-C and DBP increases correlated with increases in haemoglobin (improvement in anaemia) in patients with PNH (see section 5.1).

In patients treated with iptacopan 200 mg twice a day in the C3G clinical study, no clinically relevant differences were observed in total cholesterol, LDL-cholesterol or blood pressure compared to placebo.

Heart rate decrease in patients with PNH

In patients treated with iptacopan 200 mg twice a day in PNH clinical studies, a mean decrease in heart rate of approximately 5 bpm was seen at month 6 (mean of 68 bpm).

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

During clinical studies, a few patients took up to 800 mg iptacopan daily and this was well tolerated. In healthy volunteers, the highest dose was 1 200 mg administered as a single dose and this was well tolerated.

General supportive measures and symptomatic treatment should be initiated in cases of suspected overdose.