TYMLOS SIDE EFFECTS

SIDE EFFECTS

The following adverse reactions are described in greater detail in other sections:

• Orthostatic Hypotension
• Hypercalcemia
• Hypercalciuria and Urolithiasis

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Postmenopausal Women With Osteoporosis

The safety of TYMLOS was evaluated in a randomized, multicenter, double-blind, placebo-controlled clinical trial in postmenopausal women with osteoporosis aged 49 to 86 years (mean age 69 years) who were randomized to receive 80 mcg of TYMLOS (N = 824) or placebo (N = 821), given subcutaneously once daily for 18 months.

In this study, the incidence of all-cause mortality was 0.4% in the TYMLOS group and 0.6% in the placebo group. The incidence of serious adverse events was 10% in the TYMLOS group and 11% in the placebo group. The percentage of patients who discontinued study drug due to adverse events was 10% in the TYMLOS group and 6% in the placebo group. The most common adverse reactions leading to study drug discontinuation in the TYMLOS group were nausea (2%), dizziness (1%), headache (1%), and palpitations (1%).

Table 1 shows the most common adverse reactions in the trial. These adverse reactions were generally not present at baseline, occurred more commonly with TYMLOS than with placebo, and occurred in at least 2% of the patients treated with TYMLOS.

Table 1: Common Adverse Reactions Reported in Postmenopausal Women with Osteoporosis*

Orthostatic Hypotension

In the clinical trial of women with postmenopausal osteoporosis, the incidence of orthostatic blood pressure decline ≥20 mmHg systolic or ≥10 mmHg diastolic at 1 hour after the first injection was 4% in the TYMLOS group and 3% in the placebo group. At later time points the incidence was generally similar between the treatment groups. Adverse reactions of orthostatic hypotension were reported in 1% of patients receiving TYMLOS and 0.5% of patients receiving placebo. Dizziness was reported by more TYMLOS-treated patients (10%) compared to placebo (6%).

Tachycardia

In women with postmenopausal osteoporosis, adverse reactions of tachycardia, including sinus tachycardia, were reported in 2% of patients receiving TYMLOS and 1% of patients in the placebo group. In 5 of the 13 patients receiving TYMLOS who experienced tachycardia, symptoms occurred within 1 hour of administration. TYMLOS has been associated with a dose-dependent increase in heart rate which developed within 15 minutes after injection and resolved in about 6 hours.

Injection Site Reactions

During the first month of the trial, injection site reactions were assessed daily one-hour after injection. TYMLOS had a higher incidence than placebo of injection site redness (58% vs. 28%), edema (10% vs. 3%) and pain (9% vs. 7%). Severe redness, severe edema, and severe pain were reported among 2.9%, 0.4%, and 0.4% of the TYMLOS-treated patients.

Laboratory Abnormalities

Hypercalcemia

In the clinical trial of women with postmenopausal osteoporosis, TYMLOS caused increases in serum calcium concentrations. The incidence of hypercalcemia, defined as albumin-corrected serum calcium ≥10.7 mg/dL at 4 hours following injection at any visit was 3% in TYMLOS-treated patients and 0.1% with placebo. Pre-dose serum calcium was similar to baseline in both groups. There were 2 (0.2%) TYMLOS-treated patients and no placebo-treated patients who discontinued from the study due to hypercalcemia. The incidence of hypercalcemia with TYMLOS was higher in patients with mild or moderate renal impairment (4%) compared to patients with normal renal function (1%).

Increases In Serum Uric Acid

TYMLOS increased serum uric acid concentrations. In the postmenopausal osteoporosis trial, among patients with normal baseline uric acid concentrations, 25% of patients in the TYMLOS group and 6% of patients in the placebo group had at least one post-baseline concentration above the normal range. The hyperuricemia observed in TYMLOS-treated patients was not associated with an increase in adverse reactions of gout or arthralgia over that observed with placebo.

Hypercalciuria And Urolithiasis

In the clinical trial of women with postmenopausal osteoporosis, the overall incidence of urine calcium:creatinine ratio >400 mg/g was higher with TYMLOS than with placebo (20% vs 15%, respectively). Urolithiases were reported in 2.1% of TYMLOS-treated patients and 1.7% of placebo-treated patients.

Adverse Reactions From The Extension Study In Postmenopausal Women With Osteoporosis

Following 18 months of treatment with TYMLOS or placebo, 1139 women transitioned to treatment with alendronate 70 mg administered orally once weekly. The incidence of adverse events occurring during alendronate treatment was similar in patients with prior placebo or TYMLOS therapy.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TYMLOS in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Of the patients receiving TYMLOS for 18 months, 49% (300/610) developed anti-abaloparatide antibodies, of these, 68% (201/297) developed neutralizing antibodies to abaloparatide. Of the patients with anti-abaloparatide antibodies tested for cross-reactivity, 2.3% (7/298) developed cross-reactivity to PTHrP, 43% (3/7) developed neutralizing antibodies to PTHrP, and 0% (0/298) developed cross-reactive antibodies to PTH. Antibody formation did not appear to have any clinically significant impact on safety or efficacy endpoints, including bone mineral density (BMD) response, fracture reduction, or adverse events.

Most of the patients with anti-abaloparatide antibodies during treatment with TYMLOS, 85% (256/300), had follow-up antibody measurements six months after completion of TYMLOS therapy. Among these patients, 56% (143/256) remained antibody positive.

Postmarketing Experience

The following adverse reactions have been identified during the post-approval use of TYMLOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Abdominal distension, abdominal pain
• Constipation, diarrhea, vomiting
• Asthenia, lethargy, malaise
• Insomnia
• Hypersensitivity and anaphylactic reactions, dyspnea (in the context of allergic reactions)
• Pruritus, rash
• Generalized pain and pain in bone, joint, back, and extremity
• Muscle spasms of the leg and back
• Injection site reactions including bruising, hemorrhage, pruritus, and rash

SRC: NLM .