ONPATTRO Concentrate for solution for infusion Ref.[7631] Active ingredients: Patisiran

Infusion-related reactions

IRRs have been observed in patients treated with Onpattro. In patients experiencing an IRR, the majority experienced the first IRR within the first 2 infusions (see section 4.8). Across clinical studies, the most common symptoms (reported in ≥2% of patients) of IRRs were flushing, back pain, nausea, abdominal pain, dyspnoea, and headache. IRRs may also include hypotension and syncope.

To reduce the risk of IRRs, patients should receive premedications on the day of Onpattro infusion, at least 60 minutes prior to the start of infusion (see section 4.2). If an IRR occurs, slowing or interrupting the infusion and institution of medical management (e.g., corticosteroids or other symptomatic treatment) should be considered, as clinically indicated. If the infusion is interrupted, resumption of the infusion at a slower infusion rate may be considered after symptoms have resolved. The Onpattro infusion should be discontinued in the case of a serious or life-threatening IRR.

Some patients who experience IRRs may benefit from a slower infusion rate or additional or higher doses of one or more of the premedications with subsequent infusions to reduce the risk of IRRs.

Vitamin A deficiency

By reducing serum TTR protein, Onpattro treatment leads to a decrease in serum vitamin A (retinol) levels (see section 5.1). Serum vitamin A levels below the lower limit of normal should be corrected and any ocular symptoms or signs due to vitamin A deficiency should be evaluated prior to initiation of treatment with Onpattro.

Patients receiving Onpattro should take oral supplementation of approximately 2500 IU vitamin A per day to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Referral for ophthalmological assessment is recommended if patients develop ocular symptoms suggestive of vitamin A deficiency, including reduced night vision or night blindness, persistent dry eyes, eye inflammation, corneal inflammation or ulceration, corneal thickening or corneal perforation.

Serum vitamin A levels should not be used to guide vitamin A supplementation during treatment with Onpattro (see section 4.5).

During the first 60 days of pregnancy, both too high or too low vitamin A levels may be associated with an increased risk of foetal malformation. Therefore, pregnancy should be excluded before initiating Onpattro and women of childbearing potential should practise effective contraception. If a woman intends to become pregnant, Onpattro and vitamin A supplementation should be discontinued and serum vitamin A levels should be monitored and have returned to normal before conception is attempted.

In the event of an unplanned pregnancy, Onpattro should be discontinued (see section 4.6). Vitamin A supplementation should be discontinued during the first trimester, unless the pregnant woman has clinical signs of vitamin A deficiency. If such signs are present, vitamin A supplementation should not exceed 2500 IU per day. Thereafter, vitamin A supplementation of 2500 IU per day should be resumed in the second and third trimesters if serum vitamin A levels have not returned to normal, because of the increased risk of vitamin A deficiency in the third trimester.

Excipients

This medicinal product contains 3.99 mg sodium per mL, equivalent to 0.2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

No formal clinical drug interaction studies have been performed. Onpattro is not expected to be affected by inhibitors or inducers of cytochrome P450 enzymes or to cause drug-drug interactions, except for induction and time-dependent inhibition of CYP2B6 in vitro. The net effect on CYP2B6 substrates (e.g., bupropion and efavirenz) in vivo is unknown.

Vitamin A testing

Serum TTR is a carrier of retinol binding protein, which facilitates transport of vitamin A in the blood. Treatment with Onpattro reduces serum TTR levels, which results in reduced levels of retinol binding protein and vitamin A in the serum. However, transport and tissue uptake of vitamin A can occur through alternative mechanisms in the absence of retinol binding protein. As a result, during treatment with Onpattro, laboratory tests for serum vitamin A do not reflect the total amount of vitamin A in the body and should not be used to guide vitamin A supplementation (see sections 4.4 and 5.1).

Women of childbearing potential

Treatment with Onpattro reduces serum levels of vitamin A. Both too high or too low vitamin A levels may be associated with an increased risk of foetal malformation. Therefore, pregnancy should be excluded before initiation of treatment and women of childbearing potential should use effective contraception. If a woman intends to become pregnant, Onpattro and vitamin A supplementation should be discontinued and serum vitamin A levels should be monitored and have returned to normal before conception is attempted.

Pregnancy

There are no data on the use of Onpattro in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Due to the potential teratogenic risk arising from unbalanced vitamin A levels, Onpattro should not be used during pregnancy, unless the clinical condition of the woman requires treatment. As a precautionary measure, vitamin A and thyroid stimulating hormone (TSH) levels should be obtained early in pregnancy (see section 5.3). Close monitoring of the foetus should be carried out in the event of an unplanned pregnancy, especially during the first trimester (see section 4.4). Women of childbearing potential have to use effective contraception during treatment with Onpattro.

Breast-feeding

It is unknown whether Onpattro is excreted in human milk. Available toxicological data in animals have shown excretion of small amounts of the lipid components DLin-MC3-DMA and PEG₂₀₀₀-C-DMG in milk (see section 5.3).

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Onpattro, 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 effects of Onpattro on human fertility. No impact on male or female fertility was detected in animal studies (see section 5.3).

On the basis of the pharmacodynamic and pharmacokinetic profiles, Onpattro is considered to have no or negligible influence on the ability to drive or use machines.

Summary of the safety profile

The most frequently occurring adverse reactions reported in Onpattro-treated patients were peripheral oedema (29.7%) and infusion-related reactions (18.9%). The only adverse reaction resulting in the discontinuation of Onpattro was an infusion-related reaction (0.7%).

Tabulated list of adverse reactions

The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ Class (SOC) by frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of the adverse reactions is expressed according to the following categories: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100).

Table 1. Adverse reactions reported for Onpattro 300 micrograms per kg:

Description of selected adverse reactions

Infusion-related reactions

Symptoms of IRRs include, but are not limited to: arthralgia or pain (including back, neck, or musculoskeletal pain), flushing (including erythema of face or skin warm), nausea, abdominal pain, dyspnoea or cough, chest discomfort or chest pain, headache, rash, chills, dizziness, fatigue, increased heart rate or palpitations, hypotension which may include syncope, hypertension, facial oedema.

In clinical studies, all patients received premedication with a corticosteroid, paracetamol, and H1 and H2 blockers to reduce the risk of IRRs. In the double-blind placebo-controlled study, 18.9% of Onpattro-treated patients experienced IRRs, compared to 9.1% of placebo-treated patients. In Onpattro-treated patients, all IRRs were either mild (95.2%) or moderate (4.8%) in severity. Among Onpattro-treated patients who experienced an IRR, 78.6% experienced the first IRR within the first 2 infusions. The frequency of IRRs decreased over time. Few IRRs led to infusion interruption. IRRs resulted in permanent discontinuation of Onpattro in <1% of patients in clinical studies. For clinical management of IRRs, see section 4.4.

Peripheral oedema

In the placebo-controlled study, peripheral oedema was reported in 29.7% of Onpattro-treated patients and 22.1% of placebo-treated patients. All events were mild or moderate in severity and did not lead to treatment discontinuation. In Onpattro-treated patients, the events decreased in frequency over time.

Extravasation

Extravasation was observed in <0.5% of infusions in clinical studies. Signs and symptoms included phlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis (subcutaneous inflammation), cellulitis, erythema or injection site redness, burning sensation, or injection site pain.

Other special population(s)

Liver transplant recipients

In an open-label study in 23 hATTR amyloidosis patients with polyneuropathy progression post liver transplant, the safety profile of patisiran was consistent with previous clinical studies (see section 5.1).

Immunogenicity

Anti-drug antibodies to Onpattro were evaluated by measuring antibodies specific to PEG₂₀₀₀-C-DMG, a lipid component exposed on the surface of Onpattro. In the placebo-controlled and open-label clinical studies, 7 of 194 (3.6%) patients with hATTR amyloidosis developed anti-drug antibodies during treatment with Onpattro. One additional patient had pre-existing anti-drug antibodies. Antidrug antibody titres were low and transient with no evidence of an effect on clinical efficacy, the safety profile, or the pharmacokinetic or pharmacodynamic profiles of Onpattro.

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 national reporting system listed in Appendix V.

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