ELADYNOS Solution for injection Ref.[51680] Active ingredients: Abaloparatide

Orthostatic hypotension and increased heart rate

Orthostatic hypotension and transient episodes of increase in heart rate may occur with abaloparatide, typically within 4 hours of injection. Symptoms may include dizziness, palpitations, tachycardia, or nausea, and may resolve by having the patient lie down. The first injection(s) of abaloparatide should be performed under the guidance of an appropriately qualified health care professional who may observe the patient during the first hour after injection. Abaloparatide should always be administered where the patient can sit or lie down if necessary.

Abaloparatide may have vasodilating effect on vascular smooth muscle and positive chronotropic/inotropic effects on cardiac muscle. Individual benefit risk assessment is important. Blood pressure, cardiac status and ECG should be assessed prior to beginning treatment with abaloparatide. Patients with cardiac disease should be monitored for worsening of their disease. If severe orthostatic hypotension or severe cardiovascular symptoms occur, the treatment should be discontinued.

Hypercalcaemia

In normocalcaemic patients, transient elevations of serum calcium concentrations have been observed following abaloparatide injection. Serum calcium concentrations reach a maximum at approximately 4 hours and return to baseline by 24 hours after each dose. Therefore, if blood samples for serum calcium measurements are taken, this should be done approximately 24 hours after the most recent injection. Routine calcium monitoring during therapy is not required in patients without additional risk factors for hypercalcaemia.

Hypercalciuria and urolithiasis

Abaloparatide may cause hypercalciuria. It is unknown whether abaloparatide may exacerbate urolithiasis in patients with active or a history of urolithiasis. If active urolithiasis or pre-existing hypercalciuria is suspected, measurement of urinary calcium excretion should be considered.

Duration of treatment

The maximum total duration of treatment with abaloparatide should be 18 months. Studies in rats indicate an increased incidence of osteosarcoma with long-term administration of abaloparatide (see section 5.3).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium free’.

No dedicated clinical drug-drug interaction studies have been performed with abaloparatide. The interaction potential of abaloparatide is regarded low considering its pharmacokinetic properties.

There is no data on efficacy of abaloparatide in patients with prior or concomitant bisphosphonate or glucocorticoid treatment.

Concomitant use of vasoactive medicinal products may predispose to orthostatic hypotension since the blood pressure lowering effect of abaloparatide may be increased, see section 4.4.

Sporadic case reports have suggested that hypercalcaemia may predispose patients to digitalis toxicity. Because abaloparatide has been shown to increase serum calcium, it should be used with caution in patients taking digitalis.

This medicine is not indicated in women of childbearing potential. It is not to be used in women who are, or may be, pregnant or breast-feeding (see sections 4.1 and 4.3).

Pregnancy

Eladynos is contraindicated during pregnancy (see section 4.3).

Breast-feeding

It is unknown whether abaloparatide is excreted in human milk. A risk to the newborns/infants cannot be excluded. Eladynos is contraindicated during breast-feeding (see section 4.3).

Fertility

No data are available on the effect of abaloparatide on human fertility. Studies in rats with abaloparatide have shown no effects on male fertility (see section 5.3).

Abaloparatide has no or negligible influence on the ability to drive and use machines. Transient orthostatic hypotension or dizziness may occur following administration of abaloparatide (see section 4.8). These patients should refrain from driving or the use of machines until symptoms have subsided.

Summary of the safety profile

The most commonly reported adverse drug reactions in patients treated with abaloparatide in the ACTIVE study were hypercalciuria (15.6%), dizziness (11.1%), back pain (8.6%), nausea (8.5%), headache (8.5%), arthralgia (8.4%), hypertension (6.8%), injection site reaction (6.2%), and palpitations (5.6%).

Tabulated list of adverse reactions

Of patients in the abaloparatide ACTIVE study, 90.3% of the abaloparatide patients and 88.4% of the placebo patients reported at least 1 adverse event.

The adverse reactions associated with the use of abaloparatide in osteoporosis in the ACTIVE study and in postmarketing exposure are summarised in the table below. The following MedDRA convention has been used for the classification of the adverse reactions: 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 frequency not known (cannot be estimated from the available data).

Table 1. Tabulated list of adverse reactions:

Description of selected adverse reactions

Increased heart rate

In the QT study, the placebo-adjusted mean heart rate increase was 14.5 beats per minute (bpm) 15 minutes after administration. This increase in heart rate was most prominent during the first hour post dose but was seen up to 6 hours in some subjects.

In the ACTIVE study, heart rate was measured one hour post dose of every study visit, with median heart rate increase from pre-dose of 14 bpm in abaloparatide treated patients as compared to 7 bpm in placebo treated patients. Patients with >20 bpm increase in heart rate at 1 hour after the first dose were more likely to experience palpitations and/or increases in heart rate >20 bpm during subsequent treatment. Adverse reactions of tachycardia and sinus tachycardia were reported in 1.6% of patients receiving abaloparatide and 0.4% of patients in the placebo group.

Orthostatic hypotension

In women with postmenopausal osteoporosis, adverse reactions of orthostatic hypotension were reported in 1% of patients receiving abaloparatide and 0.6% of patients in the placebo group.

Injection site reactions

Abaloparatide can cause injection site reactions including injection site bruising, erythema, haemorrhage, hypersensitivity, pain, rash, and swelling. The overall incidence in the abaloparatide arm was 5.3% compared to 4.0% in the placebo group.

Laboratory findings

Serum calcium

Abaloparatide can cause transient increases in serum calcium levels measured 4 hours post-dose. The overall incidence of hypercalcaemia, defined as albumin-corrected serum calcium ≥2.67 mmol/L (or ≥10.7 mg/dL) in the abaloparatide arm was higher (3.3%) compared to the placebo group (0.4%).

Serum uric acid

Abaloparatide increased serum uric acid concentrations. In the ACTIVE study, 25% of patients in the abaloparatide group had normal baseline uric acid concentrations which were increased above the normal range at post-baseline, compared with 5% in the placebo group.

Hypercalciuria and urolithiasis

In the clinical trial of women with postmenopausal osteoporosis, the overall incidence of urine calcium: creatinine ratio >0.00113 mmol/µmol (or >400 mg/g) was higher with abaloparatide than with placebo (20% vs 15%, respectively). Urolithiasis was reported in 1.4% of abaloparatide-treated patients and 1.2% of placebo-treated patients.

Immunogenicity

Of the patients receiving abaloparatide for 18 months, 42.9% developed anti-abaloparatide antibodies and 28.5% developed in vitro neutralising antibodies. Formation of anti-abaloparatide antibodies is associated with increased clearance of abaloparatide. These changes in clearance could be related to antiabaloparatide antibodies interfering with the accurate measurement of abaloparatide plasma concentrations. Compared to antibody negative patients, no clinically relevant differences in safety or efficacy were observed for patients who were antibody positive or who were positive for in vitro neutralising antibodies.

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.

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