PASATRU Solution for injection Ref.[116899] Active ingredients: Garetosmab

5.1 Embryo-Fetal Toxicity

PASATRU is contraindicated during pregnancy. Based on its mechanism of action and findings from animal reproduction studies, PASATRU can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)]. Intravenous administration of garetosmab-grts to pregnant cynomolgus monkeys resulted in embryo-fetal toxicity, infant mortality, and post-natal malformations at exposures equivalent to or higher than those in patients at the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively.

For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment. Advise females of reproductive potential to use effective contraception during treatment with PASATRU and for 6 months after the last dose. Advise the patient to discontinue PASATRU immediately if pregnancy occurs during treatment and to contact their healthcare provider [see Use in Specific Populations (8.1, 8.3)].

5.2 Skin and Soft Tissue Infections

Skin and soft tissue infections requiring treatment and/or hospitalization, including abscesses and cellulitis [see Adverse Reactions (6.1)], have occurred in patients receiving PASATRU in clinical trials.

Advise patients to report signs or symptoms of skin infection, including erythema, pain, swelling, or fever, and to seek medical attention if these occur.

5.3 Epistaxis

Spontaneous epistaxis, including serious cases requiring medical intervention, has been reported in patients receiving PASATRU. In clinical trials in the FOP population, one serious case of spontaneous epistaxis occurred that required hospitalization for nasal packing and application of a clotting agent.

Advise patients to seek medical attention if they experience epistaxis that is severe, prolonged (e.g., lasting more than 20 minutes) and does not resolve with standard first-aid measures.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Skin and Soft Tissue Infections [see Warnings and Precautions (5.2)]
• Epistaxis [see Warnings and Precautions (5.3)]

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

The safety of PASATRU was evaluated in a randomized, double-blind, parallel-group, multicenter, placebo-controlled trial that enrolled a total of 63 adults with FOP. Patients received placebo or PASATRU 10 mg/kg or 3 mg/kg every 4 weeks in the 56-week double-blind treatment period then continued their originally assigned treatment in a double-blind extension phase [see Clinical Studies (14)].

Table 1 summarizes the adverse reactions occurring in ≥10% of patients treated with PASATRU (10 mg/kg or 3 mg/kg) every 4 weeks and more frequently than placebo through Week 56.

Table 1. Adverse Reactions Occurring in ≥10% of Adults with FOP Treated with PASATRU 10 mg/kg or 3 mg/kg and more Frequently than Placebo Through Week 56:

^* Abscess includes abscess, abscess limb, subcutaneous abscess, and tooth abscess.
^†Increased hair growth includes hirsutism, hypertrichosis, hair growth abnormal, and hair disorder.
^‡ Oral ulcers includes aphthous ulcer, lip ulceration, mouth ulceration, oral mucosal blistering, and stomatitis.

Clinically Significant Adverse Reactions Occurring in <10% of Adults with FOP

Cellulitis was reported in 1 (4%) patient receiving PASATRU 10 mg/kg every 4 weeks and in none of the patients receiving PASATRU 3 mg/kg every 4 weeks or placebo.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of PASATRU or of other garetosmab products.

Among patients with FOP who received PASATRU 10 mg/kg or 3 mg/kg every 4 weeks in clinical trials for up to 76 weeks, 1.3% (1/76) developed anti-garetosmab-grts antibodies.

There are insufficient data to assess whether there are clinically significant effects of anti-drug antibodies on the pharmacokinetics, safety, or effectiveness of PASATRU.

Risk Summary

PASATRU is contraindicated for use during pregnancy. Based on its mechanism of action and data from animal reproduction studies, PASATRU can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on PASATRU during pregnancy to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Although there are no data on PASATRU exposure during pregnancy, monoclonal antibodies can be actively transported across the placenta. Inhibition of activin A signaling by PASATRU during pregnancy may adversely affect embryogenesis and fetal organogenesis, including development of the reproductive system (see Clinical Considerations).

In an enhanced pre- and post-natal developmental (ePPND) toxicity study, intravenous administration of garetosmab-grts to pregnant cynomolgus monkeys resulted in developmental toxicity, including post-natal malformations, neurobehavioral deficits, and infant mortality at exposures equivalent to or higher than those in patients at the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively (see Data). If pregnancy occurs during treatment with PASATRU, discontinue treatment immediately, and advise the patient to contact their healthcare provider.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Therefore, it is expected that PASATRU may be present in infants exposed in utero. The potential clinical impact of PASATRU exposure in infants exposed in utero should be considered.

Data

Animal Data

In an ePPND toxicity study, pregnant cynomolgus monkeys were administered intravenous doses of garetosmab-grts 5 mg/kg or 50 mg/kg once weekly beginning from gestation day 20 through delivery, with no evidence of maternal toxicity at either dose level. An increased incidence of post-natal malformations, including neurological deficiencies and testes malformations, were observed in offspring at 5 mg/kg/week (approximately equivalent to or 4 times the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively, based on area under the concentration curve [AUC]). Increased incidences of stillbirth, premature delivery, post-natal malformations including generalized alopecia, and infant mortality were observed in offspring of pregnant monkeys receiving treatment with garetosmab-grts at 50 mg/kg/week (approximately 9 times or 31 times the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively, based on AUC).

Risk Summary

There are no data on the presence of PASATRU in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to PASATRU are unknown. Because of the potential for serious adverse reactions of PASATRU absorption in the breastfed infant, including skin and soft tissue infections, and the potential for effects on male reproductive organ development based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with PASATRU and for 6 months after the last dose.

Based on animal data and mechanism of action, PASATRU can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].

Pregnancy Testing

Verify that the patient is not pregnant prior to initiating PASATRU [see Dosage and Administration (2.1)].

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with PASATRU and for 6 months after the last dose of PASATRU.

Infertility

Males

Based on findings from animal studies, PASATRU may impair male fertility [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of PASATRU have not been established in pediatric patients.

Clinical studies of PASATRU did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.