Abaloparatide

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

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.

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.

Abaloparatide is contraindicated during pregnancy.

It is unknown whether abaloparatide is excreted in human milk. A risk to the newborns/infants cannot be excluded. Abaloparatide is contraindicated during breast-feeding.

This medicine is not indicated in women of childbearing potential.

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.

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. 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).

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.