Rybelsus

Overview of RYBELSUS Formulations

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There are two RYBELSUS formulations (i.e., formulation R1 and formulation R2) with different recommended dosages. Refer to recommendations on how to switch from one formulation to another formulation [see Dosage and Administration ( 2.3, 2.4)].

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RYBELSUS (formulation R1) includes strengths 3 mg, 7 mg and 14 mg.

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RYBELSUS (formulation R2) includes strengths 1.5 mg, 4 mg and 9 mg.

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These formulations are not substitutable on a mg per mg basis.

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Use either RYBELSUS formulation R1or formulation R2; do not use both formulations at the same time.

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Do not take more than one tablet per day.

Important Administration Instructions

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Take RYBELSUS on an empty stomach in the morning with water (up to 4 ounces of water). Do not take RYBELSUS with other liquids besides water.

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After taking RYBELSUS, wait at least 30 minutes before eating food, drinking beverages or taking other oral medications [see Clinical Pharmacology ( 12.3)].

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Swallow tablets whole. Do not split crush or chew.

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If a dose is missed, skip the missed dose and take the next dose the following day.

Recommended Starting, Escalation and Maintenance Dosage of RYBELSUS Formulations R1 and R2

RYBELSUS (formulation R1)

RYBELSUS (formulation R1) includes the following strengths: 3 mg, 7 mg and 14 mg.

Recommend the following RYBELSUS (formulation R1) dosage to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.6), Adverse Reactions ( 6.1)]:

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Starting Dosage (Initiation Phase) (Days 1 to 30): The recommended starting dosage is 3 mg orally once daily (this dosage is not effective for glycemic control).

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Escalation and Maintenance Dosage (Days 31 and beyond):

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Days 31 to 60: Increase the dosage to 7 mg orally once daily.

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On Day 61 or thereafter, if:

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No additional glycemic control is needed, maintain the dosage at 7 mg orally once daily.

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Additional glycemic control is needed, increase the dosage to 14 mg orally once daily.

RYBELSUS (formulation R2)

RYBELSUS (formulation R2) includes the following strengths: 1.5 mg, 4 mg and 9 mg.

Recommend the following RYBELSUS (formulation R2) dosage to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.6), Adverse Reactions ( 6.1)]:

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Starting Dosage (Initiation Phase) (Days 1 through 30): The recommended starting dosage is 1.5 mg orally once daily (this dosage is not effective for glycemic control).

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Escalation and Maintenance Dosage (Days 31 and beyond):

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Days 31 to 60: Increase the dosage to 4 mg orally once daily.

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On Day 61 or thereafter, if:

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No additional glycemic control is needed maintain the dosage at 4 mg orally once daily.

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Additional glycemic control is needed increase the dosage to 9 mg orally once daily.

Switching Between RYBELSUS (Formulations R1 or R2) or from OZEMPIC to RYBELSUS

Switching Between RYBELSUS Formulations

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Do not switch between RYBELSUS formulations during the initiation phase (Days 1-30) [see Dosage and Administration ( 2.3)].

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After 30 days of RYBELSUS treatment (after the initiation phase) [see Dosage and Administration ( 2.3)], patients may switch between RYBELSUS formulations (see Table 1).

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When switching between the formulations, initiate the other RYBELSUS formulation the day after discontinuing the previous RYBELSUS formulation.

 

Table 1. Switching Between Escalation or Maintenance Dosage of RYBELSUS Formulations

 

*Discontinue this formulation and initiate the alternate formulation the day after

Switching from OZEMPIC to RYBELSUS (formulation R1) or RYBELSUS (formulation R2)

Switching from OZEMPIC to RYBELSUS (formulation R1)

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One week after discontinuing 0.5 mg of subcutaneous OZEMPIC, start 7 mg or 14 mg of RYBELSUS (formulation R1) orally once daily.

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Switching recommendations for patients taking Ozempic 0.25 mg, 1 mg or 2 mg subcutaneously once weekly to RYBELSUS (formulation R1) are not available.

Switching from OZEMPIC to RYBELSUS (formulation R2)

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One week after discontinuing 0.5 mg of subcutaneous OZEMPIC, start 4 mg or 9 mg of RYBELSUS (formulation R2) orally once daily.

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Switching recommendations for patients taking Ozempic 0.25 mg, 1 mg or 2 mg subcutaneously once weekly to RYBELSUS (formulation R2) are not available.

Pregnancy

Risk Summary

Available data with RYBELSUS use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be potential risks to the fetus from exposure to RYBELSUS during pregnancy. RYBELSUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In pregnant rats administered semaglutide during organogenesis, embryofetal mortality, structural abnormalities and alterations to growth occurred at maternal exposures below the maximum recommended human dose (MRHD) based on AUC. In rabbits and cynomolgus monkeys administered semaglutide during organogenesis, early pregnancy losses and structural abnormalities were observed at exposure below the MRHD (rabbit) and ≥10-fold the MRHD (monkey). These findings coincided with a marked maternal body weight loss in both animal species (see Data).

The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20 to 25% in women with a HbA1c >10. 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

Disease Associated Maternal and Fetal Risk: Poorly controlled diabetes during pregnancy increases the maternal risk for diabetic ketoacidosis, pre- eclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth and macrosomia related morbidity.

Data

Animal Data: In a combined fertility and embryofetal development study in rats, subcutaneous doses of 0.01, 0.03 and 0.09 mg/kg/day (0.2-, 0.7- and 2.1-fold the MRHD) were administered to males for 4 weeks prior to and throughout mating and to females for 2 weeks prior to mating, and throughout organogenesis to Gestation Day 17. In parental animals, pharmacologically mediated reductions in body weight gain and food consumption were observed at all dose levels. In the offspring, reduced growth and fetuses with visceral (heart blood vessels) and skeletal (cranial bones, vertebra, ribs) abnormalities were observed at the human exposure.

In an embryofetal development study in pregnant rabbits, subcutaneous doses of 0.0010, 0.0025 or 0.0075 mg/kg/day (0.06-, 0.6- and 4.4-fold the MRHD) were administered throughout organogenesis from Gestation Day 6 to 19. Pharmacologically mediated reductions in maternal body weight gain and food consumption were observed at all dose levels. Early pregnancy losses and increased incidences of minor visceral (kidney, liver) and skeletal (sternebra) fetal abnormalities were observed at ≥0.0025 mg/kg/day, at clinically relevant exposures.

In an embryofetal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075 and 0.15 mg/kg twice weekly (1.9-, 9.9- and 29-fold the MRHD) were administered throughout organogenesis, from Gestation Day 16 to 50. Pharmacologically mediated, marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with the occurrence of sporadic abnormalities (vertebra, sternebra, ribs) at ≥0.075 mg/kg twice weekly (≥9X human exposure).

In a pre- and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0.015, 0.075 and 0.15 mg/kg twice weekly (1.3-, 6.4- and 14-fold the MRHD) were administered from Gestation Day 16 to 140. Pharmacologically mediated marked initial maternal body weight loss and reductions in body weight gain and food consumption coincided with an increase in early pregnancy losses and led to delivery of slightly smaller offspring at ≥0.075 mg/kg twice weekly (≥6X human exposure).

Salcaprozate sodium (SNAC), an absorption enhancer in RYBELSUS, crosses the placenta and reaches fetal tissues in rats. In a pre- and postnatal development study in pregnant Sprague Dawley rats, SNAC was administered orally at 1,000 mg/kg/day (exposure levels were not measured) on Gestation Day 7 through lactation day 20. An increase in gestation length, an increase in the number of stillbirths and a decrease in pup viability were observed.

Lactation

Risk Summary

A clinical lactation study reported semaglutide concentrations below the lower limit of quantification in human breast milk. However, salcaprozate sodium (SNAC) and/or its metabolites are present in human milk. Since the activity of enzymes involved in SNAC clearance may be lower in infants compared to adults, higher SNAC plasma levels may occur in neonates and infants. Because of the unknown potential for serious adverse reactions in the breastfed infant due to the possible accumulation of SNAC, and because there are alternative formulations of semaglutide that do not contain SNAC that can be used during lactation, advise patients that breastfeeding is not recommended during treatment with RYBELSUS.

Females and Males of Reproductive Potential

Discontinue RYBELSUS in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide [see Use in Specific Populations ].

Pediatric Use

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

Geriatric Use

In the pool of glycemic control trials, 1,229 (30%) RYBELSUS-treated patients were 65 years of age and over and 199 (5%) RYBELSUS-treated patients were 75 years of age and over [see Clinical Studies ]. In PIONEER 6, the cardiovascular outcomes trial, 891 (56%) RYBELSUS-treated patients were 65 years of age and over and 200 (13%) RYBELSUS-treated patients were 75 years of age and over.

No overall differences in safety or effectiveness for RYBELSUS have been observed between patients 65 years of age and older and younger adult patients.

Renal Impairment

The recommended dosage of RYBELSUS in patients with renal impairment is the same as those with normal renal function.

The safety and effectiveness of RYBELSUS was evaluated in a 26-week clinical study that included 324 patients with moderate renal impairment (eGFR 30 to 59 mL/min/1.73 m2) [see Clinical Studies ]. In patients with renal impairment including end-stage renal disease (ESRD), no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology ].

Hepatic Impairment

The recommended dosage in patients with hepatic impairment is the same as those with normal hepatic function.

In a study in subjects with different degrees of hepatic impairment, no clinically relevant change in semaglutide pharmacokinetics was observed [see Clinical Pharmacology ].