Tymlos

Name: Tymlos

Side effects

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

  • Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
  • Hypercalcemia [see WARNINGS AND PRECAUTIONS]
  • Hypercalciuria and Urolithiasis [see WARNINGS AND PRECAUTIONS]

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 [see Clinical Studies].

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*

Preferred term TYMLOS
(N=822) (%)
Placebo
(N=820) (%)
Hypercalciuria 11 9
Dizziness 10 6
Nausea 8 3
Headache 8 6
Palpitations 5 0.4
Fatigue 3 2
Abdominal pain upper 3 2
Vertigo 2 2
* Adverse reactions reported in ≥ 2% of TYMLOS-treated patients.

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%) [see WARNINGS AND PRECAUTIONS].

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 [see CLINICAL PHARMACOLOGY].

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 [see WARNINGS AND PRECAUTIONS]. 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 [see Clinical Studies].

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, immune-related hypersensitivity or allergic reactions, or other 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.

Adverse Effects

>10%

Injection site redness (58%)

Hypercalciuria (11%)

1-10%

Dizziness (10%)

Injection site edema (10%)

Nausea (8%)

Headache (8%)

Palpitations (5%)

Orthostatic hypotension (4%)

Fatigue (3%)

Upper abdominal pain (3%)

Hypercalcemia (3%)

Vertigo (2%)

Tachycardia (2%)

Pregnancy

Pregnancy

Not indicated for females of reproductive potential

Lactation

Not indicated for females of reproductive potential

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Pharmacology

Mechanism of Action

Synthetic peptide analog of human parathyroid hormone-related protein (hPTHrP); hPTHrP is a naturally occurring hormone that, among other functions, regulates bone formation

Elicits anabolic effect on bone, demonstrated by increases in bone mineral density and content that correlated with increases in bone strength at vertebral and/or nonvertebral sites

Absorption

Absolute bioavailability: 36%

Peak plasma time: 0.51 hr

Peak plasma concentration: 312 pg/mL

AUC: 1622 pg·hr/mL

Distribution

Protein bound: 70%

Vd: ~50 L

Metabolism

No specific metabolism or excretion studies have been performed

Metabolism is consistent with nonspecific proteolytic degradation into smaller peptide fragments, followed by elimination by renal clearance

Elimination

Half-life: 1.7 hr

Excretion: Primarily in urine

Commonly used brand name(s)

In the U.S.

  • Tymlos

Available Dosage Forms:

  • Solution

Therapeutic Class: Endocrine-Metabolic Agent

What do I need to tell my doctor BEFORE I take Tymlos?

  • If you have an allergy to this medicine (Tymlos) or any part of this medicine.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have any of these health problems: High calcium levels or overactive parathyroid gland.

This is not a list of all drugs or health problems that interact with this medicine (Tymlos).

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of high calcium levels like weakness, confusion, feeling tired, headache, upset stomach and throwing up, hard stools (constipation), or bone pain.
  • Very bad dizziness or passing out.
  • A fast heartbeat.
  • A heartbeat that does not feel normal.
  • Very upset stomach or throwing up.
  • Back pain, belly pain, or blood in the urine. May be signs of a kidney stone.
  • Pain when passing urine.

Tymlos Description

Tymlos injection for subcutaneous administration contains abaloparatide, a synthetic 34 amino acid peptide. Abaloparatide is an analog of human parathyroid hormone related peptide, PTHrP(1-34). It has 41% homology to hPTH(1-34) (human parathyroid hormone 1-34) and 76% homology to hPTHrP(1-34) (human parathyroid hormone-related peptide 1-34).

Abaloparatide has a molecular formula of C174 H300 N56 O49 and a molecular weight of 3961 daltons with the amino acid sequence shown below:

  Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

Tymlos injection is supplied as a sterile, colorless, clear solution in a glass cartridge which is pre-assembled into a disposable single-patient-use pen. The pen is intended to deliver 30 once daily abaloparatide doses of 80 mcg in 40 mcL. Each cartridge contains 1.56 mL of Tymlos solution. Each mL contains 2000 mcg abaloparatide and the following inactive ingredients: 5 mg phenol, 5.08 mg sodium acetate trihydrate, 6.38 mg acetic acid, and water for injection.

Tymlos - Clinical Pharmacology

Mechanism of Action

Abaloparatide is a PTHrP(1-34) analog which acts as an agonist at the PTH1 receptor (PTH1R). This results in activation of the cAMP signaling pathway in target cells. In rats and monkeys, abaloparatide had an anabolic effect on bone, demonstrated by increases in BMD and bone mineral content (BMC) that correlated with increases in bone strength at vertebral and/or nonvertebral sites [see Nonclinical Toxicology (13.2)].

Pharmacodynamics

Effects on Markers of Bone Turnover

A dose-finding study of abaloparatide administered once daily for 24 weeks demonstrated a dose-response relationship for BMD and bone formation markers.

Daily administration of Tymlos to postmenopausal women with osteoporosis in clinical studies increased the bone formation marker serum procollagen type I N-propeptide (PINP). The increase in PINP levels peaked at Month 1 at 93% above baseline then decreased slowly over time. The increase in PINP was maintained above baseline throughout the treatment duration. At Month 18, PINP concentrations were approximately 45% above baseline. The increase in the bone resorption marker serum collagen type I cross-linked C-telopeptide (sCTX) peaked at Month 3 at 43% above baseline then decreased to 20% above baseline by Month 18.

Cardiac Electrophysiology

A 4-way cross-over thorough QT/QTc study was conducted in 55 healthy subjects who received single doses of placebo, subcutaneous doses of abaloparatide at 80 mcg and 240 mcg (three times the recommended dose), and moxifloxacin 400 mg orally. Abaloparatide increased heart rate, with a mean peak increase of 15 beats per minute (bpm) and 20 bpm at the first time point (15 minutes) after dosing with 80 mcg and 240 mcg, respectively. There were no clinically meaningful effects of abaloparatide on QTcI (individually corrected QT intervals) or cardiac electrophysiology.

Pharmacokinetics

Following seven days of subcutaneous administration of abaloparatide 80 mcg, the mean (SD) abaloparatide exposure was 812 (118) pg/mL for Cmax and 1622 (641) pg·hr/mL for AUC0-24.

Figure 1 below shows the mean (SD) abaloparatide pharmacokinetic profile in postmenopausal women (N = 8) on Day 7.


Figure 1. Mean Abaloparatide Pharmacokinetic Profile in Postmenopausal Women on Day 7

Absorption

The median (range) time to peak concentration of abaloparatide 80 mcg was 0.51 hr (0.25 to 0.52 hr) following subcutaneous administration. The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%.

Distribution
The in vitro plasma protein binding of abaloparatide was approximately 70%. The volume of distribution was approximately 50 L.

Elimination
The mean (SD) half-life of abaloparatide is 1.7 (0.7) hrs. The peptide fragments are primarily eliminated through renal excretion.

Metabolism
No specific metabolism or excretion studies have been performed with Tymlos. The metabolism of abaloparatide is consistent with non-specific proteolytic degradation into smaller peptide fragments, followed by elimination by renal clearance.

Specific Populations

Geriatric Patients
No age-related differences in abaloparatide pharmacokinetics were observed in postmenopausal women ranging from 49 to 86 years of age.

Race
No differences in abaloparatide pharmacokinetics based on race were observed in clinical trials.

Patients with Renal Impairment
A single 80 mcg subcutaneous dose of abaloparatide was administered to male and female patients with renal impairment: 8 patients with mild renal impairment (CLCr 60 to 89 mL/min), 7 patients with moderate renal impairment (CLCr 30 to 59 mL/min), 8 patients with severe renal impairment (CLCr 15 to 29 mL/min), and 8 healthy subjects with normal renal function (CLCr 90 or greater mL/min) matched by sex, age, and body mass index (BMI). Abaloparatide Cmax increased 1.0-, 1.3-, and 1.4-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Abaloparatide AUC increased 1.2-, 1.7-, and 2.1-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Patients undergoing dialysis were not included in the study.

Drug Interactions

In vitro studies showed that abaloparatide, at therapeutic concentrations, does not inhibit or induce Cytochrome P450 enzymes.

PRINCIPAL DISPLAY PANEL - NDC 70539-001-02 - 80 mcg Carton Label



PRINCIPAL DISPLAY PANEL - NDC 70539-001-99 - Sample 80 mcg Prefilled Pen Label



What is Tymlos?

Tymlos (abaloparatide) is a man-made form of a hormone called parathyroid that exists naturally in the body. Abaloparatide increases bone density and increases bone strength to help prevent fractures.

Tymlos is used to treat osteoporosis in postmenopausal women who have a high risk of bone fracture.

Tymlos may also be used for purposes not listed in this medication guide.

What are some other side effects of this drug?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Dizziness.
  • Upset stomach.
  • Headache.
  • Feeling tired or weak.
  • Belly pain.
  • Irritation where the shot is given.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

(web3)