There are no data from the use of olipudase alfa in pregnant women. Studies in animals have shown reproductive toxicity. Olipudase alfa is not recommended during pregnancy and in women of childbearing potential not using contraception, unless the potential benefits to the mother outweigh the potential risks, including those to the foetus.
It is unknown whether olipudase alfa is excreted in human milk. There is insufficient information on the excretion of olipudase alfa in animal milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue olipudase alfa therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
No human data are available on the effects of olipudase alfa on male and female fertility. Animal data do not indicate direct or indirect harmful effects with respect to fertility.
Because hypotension has been reported in clinical studies, olipudase alfa may have minor influence on the ability to drive and use machines.
Serious adverse reactions reported in patients treated with olipudase alfa were an event of extrasystoles in the context of a history of cardiomyopathy in 1 (2.5%) adult patient, and anaphylactic reaction, urticaria, rash, hypersensitivity, and alanine aminotransferase level increase, each in 1 (5%) paediatric patient. The incidence of serious hypersensitivity-related IARs were higher in paediatric patients compared to adults
The most frequently reported adverse drug reactions (ADRs) were headache (31.7%), pyrexia (25%), urticaria (21.7%), nausea (20%), vomiting (16.7%), abdominal pain (15%), myalgia (11.7%), pruritus (10%) and C-reactive protein increased (10%).
The pooled safety analysis from 4 clinical studies (a tolerability study in adult patients, ASCEND, ASCEND-Peds, and an extension study in adult and paediatric patients) included a total of 60 patients (40 adult and 20 paediatric patients) treated with olipudase alfa at doses up to 3 mg/kg every 2 weeks.
Adverse reactions reported in the pooled safety analysis of clinical studies are listed in the table below per System Organ Class, presented by frequency 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) and not known (cannot be estimated from the available data).
Adverse drug reactions in patients treated with olipudase alfa in pooled analysis of clinical studies:
| System Organ Class | Frequency | |
|---|---|---|
| Very common | Common | |
| Immune system disorders | Anaphylaxis and hypersensitivity | |
| Nervous system disorders | Headache | |
| Eye disorders | Ocular hyperaemia, ocular discomfort, eye pruritus | |
| Cardiac disorders | Palpitations, tachycardia | |
| Vascular disorders | Hypotension, hot flush, flushing | |
| Respiratory, thoracic, and mediastinal disorders | Pharyngeal oedema, pharyngeal swelling, throat tightness, wheezing, larynx irritation, dyspnoea, throat irritation | |
| Gastrointestinal disorders | Nausea, abdominal pain, vomiting | Diarrhoea, abdominal pain upper, abdominal discomfort, gastrointestinal pain |
| Hepatobiliary disorders | Hepatic pain | |
| Skin and subcutaneous tissue disorders | Urticaria, pruritus | Angioedema, fixed eruption, rash, rash papular, rash macular, rash maculopapular, rash erythematous, rash pruritic, rash morbilliform, papule, macule, erythema |
| Musculoskeletal and connective tissue disorders | Myalgia | Bone pain, arthralgia, back pain |
| General disorders and administration site conditions | Pyrexia | Pain, chills, catheter site pain, catheter site related reaction, catheter site pruritus, catheter site swelling, fatigue, asthenia |
| Investigations | C-reactive protein increased | Alanine aminotransferase increased, aspartate aminotransferase increased, serum ferritin increased, C-reactive protein abnormal, body temperature increased |
IARs were reported in 55% of adult and 65% of paediatric patients. IAR symptoms reported most frequently in adult patients were headache (22.5%), nausea (15%), urticaria (12.5%), arthralgia (10%), myalgia (10%), pyrexia (10%), pruritus (7.5%), vomiting (7.5%), and abdominal pain (7.5%). IAR symptoms reported most frequently in paediatric patients were pyrexia (40%), urticaria (35%), vomiting (30%), headache (20%), nausea (20%), and rash (15%). IARs typically occurred between the time of infusion and 24 hours after infusion end.
Hypersensitivity-related IARs, including anaphylaxis, occurred in 26.7% patients, 17.5% adult and 45% paediatric patients in clinical studies. The most frequently reported hypersensitivity-related IAR symptoms were urticaria (20%), pruritus (6.7%), erythema (6.7%), and rash (5%).
One paediatric patient in the clinical studies incurred a severe anaphylactic reaction. Also, independent of the clinical study program, a 16-month-old patient with ASMD type A treated with olipudase alfa experienced 2 anaphylactic reactions. Anti-olipudase alfa IgE antibodies were detected in both patients.
In 2 adults and 3 paediatric patients, IAR symptoms were associated with changes in laboratory parameters (e.g C-reactive protein, ferritin value) indicative of acute phase reaction.
Transient transaminase (ALT or AST) elevations within 24 to 48 hours after an infusion occurred in some patients treated with olipudase alfa during the dose escalation phase in the clinical studies. These elevations generally returned to the previous pre-infusion transaminase levels by the next scheduled infusion.
Overall, after 52 weeks of treatment with olipudase alfa, mean ALT decreased 45.9% and mean AST decreased 40.2%, compared to baseline. In adult patients, all 16 patients with an elevated baseline ALT had an ALT within the normal range and 10 of 12 patients with an elevated baseline AST had an AST within the normal range.
Overall, 16 out of 40 (40%) adult patients and 13 out of 20 (65%) paediatric patients treated with olipudase alfa developed treatment-emergent antidrug antibodies (ADA). The median time to seroconversion from first olipudase alfa infusion was approximately 33 weeks in adults and 10 weeks in paediatric patients. The majority of ADA-positive patients (11 out of 16 adult and 8 out of 13 paediatric patients) had a low ADA response (≤400) or reverted to ADA-negative. Four out of the 16 adult ADA-positive patients and 5 out of the 13 paediatric ADA-positive patients had Neutralizing Antibodies (NAb) that inhibited the olipudase alfa activity. Six patients developed NAbs at a single time point and 3 patients had an intermittent response. One paediatric patient had a treatment boosted ADA response. One paediatric patient experienced an anaphylactic reaction and developed IgE ADA, and IgG ADA with a peak titer of 1600.
No effect of ADA was observed on pharmacokinetics and efficacy of olipudase alfa in adult and paediatric populations. There was a higher percentage of patients with treatment-emergent IARs (including hypersensitivity reactions) in patients who developed treatment-emergent ADA versus those who did not (75.9% versus 41.9%).
Except for a higher incidence of hypersensitivity-related IARs in paediatric patients compared to adults, the safety profile of olipudase alfa in paediatric and adult patients was similar.
Overall, the pattern of adverse events observed in adult and paediatric patients in longer term use was consistent with that observed during the first year of treatment.
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