Overview
Overview
Cagrilintide + Semaglutide is a dual‑agonist combination blending an amylin analog (cagrilintide) with a GLP‑1 receptor agonist (Semaglutide). Clinical trials demonstrate superior weight reduction versus either agent alone, with the combination targeting complementary satiety pathways[1][2]. This educational protocol presents a once‑weekly subcutaneous approach using a practical dilution for clear insulin‑syringe measurements. Reconstitute: Add 3.0 mL bacteriostatic water → ~3.33 mg/mL total (1
- Category
- Weight Loss
- Routes
- subcutaneous
Mechanism
Cagrilintide
Mechanism of action
Mechanism of action
Cagrilintide mimics amylin , a hormone the pancreas releases with insulin to tell the brain that the body is full. The compound is engineered to last about 7-8 days in the body so it can be dosed once a week, instead of needing multiple injections like the natural hormone. Pharmacologically, cagrilintide is a dual amylin and calcitonin receptor agonist (DACRA) — meaning it activates two related receptor systems at once. Amylin receptors are concentrated in brain regions that handle fullness signals, including the area postrema and hypothalamus. When cagrilintide activates them, appetite drops and the sensation of fullness lasts longer between meals. Animal evidence suggests this pathway also helps preserve lean mass during weight reduction, although the human data is still maturing. The calcitonin receptor adds a second effect. It slows gastric emptying — meaning food leaves the stomach more slowly — which extends post-meal fullness. It is also linked to lower glucagon release after meals, which can improve glycemic stability. GLP-1 drugs (semaglutide, tirzepatide) act on a different receptor system that overlaps but is not identical to amylin signaling. Stacking the two creates additive appetite suppression rather than redundant signaling. This is the pharmacological basis for CagriSema : in REDEFINE 1, the combination produced 20.4% mean weight loss versus 11.8% for cagrilintide alone and 14.9% for semaglutide alone.
Key research findings
- 01
Cagrilintide is a long-acting, once-weekly amylin analog (an amylin/calcitonin receptor agonist) studied as an injectable clinical candidate (mechanistic / human study).
- 02
In adults with overweight or obesity, cagrilintide as a single agent produced dose-dependent body-weight reduction in controlled trials (human study, Phase 2).
- 03
In the Phase 3a REDEFINE program, the co-formulation with semaglutide (CagriSema) was associated with roughly 20% mean body-weight reduction at 68 weeks, versus about 11.5% for cagrilintide alone and about 14.9% for semaglutide alone (human study; reported 2025, New England Journal of Medicine).
- 04
Gastrointestinal effects were the most commonly observed effects in research with the combination (human study observation).
- 05
As of early-to-mid 2026, the developer indicated a regulatory filing for the semaglutide combination was planned; cagrilintide as a standalone agent remained investigational.
Primary source: REDEFINE 1 (Phase 3a, NEJM 2025): Garvey et al., n=3,417, 68 weeks. Cagrilintide monotherapy: 11.8% mean weight loss vs 2.3% placebo. CagriSema: 20.4% vs semaglutide 14.9%. Trial-product estimand. REDEFINE 2 (Phase 3a, NEJM 2025): Davies et al., n=1,206, 68 weeks, T2D + BMI ≥27. CagriSema: 13.7% body-weight reduction and 1.91 percentage-point HbA1c reduction vs placebo. REDEFINE 4 (Phase 3, Feb 2026 readout): Open-label vs tirzepatide. CagriSema: 23.0% at 84 weeks vs tirzepatide 15 mg: 25.5%. Noninferiority endpoint not met. Lancet 2021 Phase 2 (monotherapy): Lau et al., n=706, 26 weeks. Cagrilintide 0.3-4.5 mg vs liraglutide 3 mg/day. 4.5 mg arm: 10.8% mean loss; 2.4 mg arm: 9.7%; liraglutide: 9.0%; placebo: 3.0%. Lancet 2021 Phase 1b (cagri + sema): Enebo et al., n=96, 20 weeks. Established additive effect of cagrilintide + semaglutide vs semaglutide alone (17.1% vs 9.8%). Lancet 2023 Phase 2 (T2D): Frias et al., n=92, 32 weeks. CagriSema: 15.6% weight loss and 2.2 pp HbA1c reduction. Cagrilintide alone: 8.1%. Semaglutide alone: 5.1%. Mechanism and pharmacology: Kruse et al. (J Med Chem 2021) characterized the C-20 fatty diacid spacer that extends the half-life. Fletcher et al. (Nature Communications 2025) mapped cagrilintide binding to amylin and calcitonin receptors structurally. Cardiovascular signal: Gabe et al. (Diabetes Obes Metab 2024) found no clinically relevant QTc prolongation. REDEFINE 3 cardiovascular outcomes trial is ongoing (~7,000 participants). Evidence Gap
Pharmacokinetic profile
Single-dose plasma curve over 24h. Shaded band = commonly-cited therapeutic window. Illustrative only.
Researched Effects
Researched benefits
Areas of active research and investigation. Results may vary and are based on preclinical or early clinical data.
Weight reduction: Phase 2 trials report mean body‑weight loss of ~15–17% at 32 weeks with the combination, exceeding Semaglutide monotherapy[2].
Glycemic control: In type 2 diabetes, HbA1c reductions were observed alongside weight loss[1].
Protocol Reference
Protocol reference
Commonly cited research range: 0.6–4.5 mg, weekly.
Reference figures reported in the research literature — not a dosing recommendation. For interactive vial math and scheduling, see the Calculator and Schedule tabs.
Cited protocol & reconstitution guide
Source-backed reference fields by phase, including any volume fields authored in the cited guide.
Weeks 1–4 (Initiation)
Cagrilintide 0.25 mg + Semaglutide 0.25 mg
Weeks 5–8 (Early escalation)
Cagrilintide 0.5 mg + Semaglutide 0.5 mg
Weeks 9–12 (Mid escalation)
Cagrilintide 1.0 mg + Semaglutide 1.0 mg
Weeks 13–16 (Late escalation)
Cagrilintide 1.7 mg + Semaglutide 1.7 mg
Weeks 17+ (Maintenance)
Cagrilintide 2.4 mg + Semaglutide 2.4 mg
| Phase | Reference amount | Component amounts | Units / volume |
|---|---|---|---|
| Weeks 1–4 (Initiation) | Cagrilintide 0.25 mg + Semaglutide 0.25 mg | 0.25 mg cagrilintide + 0.25 mg semaglutide (0.5 mg combined per draw) | 10 units (0.10 mL) |
| Weeks 5–8 (Early escalation) | Cagrilintide 0.5 mg + Semaglutide 0.5 mg | 0.5 mg cagrilintide + 0.5 mg semaglutide (1.0 mg combined per draw) | 20 units (0.20 mL) |
| Weeks 9–12 (Mid escalation) | Cagrilintide 1.0 mg + Semaglutide 1.0 mg | 1.0 mg cagrilintide + 1.0 mg semaglutide (2.0 mg combined per draw) | 40 units (0.40 mL) |
| Weeks 13–16 (Late escalation) | Cagrilintide 1.7 mg + Semaglutide 1.7 mg | 1.7 mg cagrilintide + 1.7 mg semaglutide (3.4 mg combined per draw) | 68 units (0.68 mL) |
| Weeks 17+ (Maintenance) | Cagrilintide 2.4 mg + Semaglutide 2.4 mg | 2.4 mg cagrilintide + 2.4 mg semaglutide (4.8 mg combined per draw) | 96 units (0.96 mL) |
Titration protocol
- Weeks 1–4 (Initiation)StartCagrilintide 0.25 mg + Semaglutide 0.25 mg once weekly
Titration steps up every 4 weeks across roughly the first 16 weeks. Fix one weekday and keep it for the whole schedule.
- Weeks 5–8 (Early escalation)BuildCagrilintide 0.5 mg + Semaglutide 0.5 mg once weekly
Hold this step the full 4 weeks before stepping up.
- Weeks 9–12 (Mid escalation)BuildCagrilintide 1.0 mg + Semaglutide 1.0 mg once weekly
Hold this step the full 4 weeks. Rotate injection sites between weekly draws.
- Weeks 13–16 (Late escalation)BuildCagrilintide 1.7 mg + Semaglutide 1.7 mg once weekly
Hold this step the full 4 weeks before moving to the maintenance step.
- Weeks 17+ (Maintenance)MaintenanceCagrilintide 2.4 mg + Semaglutide 2.4 mg once weekly
Fixed-ratio pre-blend: both compounds come from a single 0.96 mL draw, so no second syringe or staggered timing is needed. Use a 1 mL U-100 syringe at this volume and keep rotating sites. One 10 mg combined vial at 2.0 mL yields 2 full maintenance draws with about 0.4 mg combined residual.
Storage & Handling
Storage requirements(typical for most peptides)
Can be stored for extended periods. Protect from moisture.
Store in refrigerator door. Never freeze after reconstitution.
Label vials with reconstitution date. Discard if cloudy.
Reconstitution steps
- 01🌡️Wash your hands and lay out a clean work surface
- 02🧴Wipe the rubber stopper of the vial with an alcohol swab and let it dry
- 03💉Draw 1 mL bacteriostatic water into a sterile syringe — this 5 mg vial yields 5 mg/mL.
- 04💧Inject the bacteriostatic water down the inside wall of the peptide vial — do not spray directly onto the lyophilized powder
- 05🔄Swirl gently until the powder is fully dissolved; do not shake
- 06🏷️Refrigerate at 36–46 °F (2–8 °C), protected from light, and use within the supplier-specified stability window
- 07❄️Important: This guide is for educational purposes only and is not medical advice. For research use only. Not for human consumption.
Additional storage notes
Store at −20 °C (−4 °F) in dry, dark conditions; minimize moisture exposure.
Refrigerate at 2–8 °C (35.6–46.4 °F); use within 30 days and avoid freeze–thaw .
Allow vials to reach room temperature before opening to reduce condensation uptake.
Clinical Evidence
Clinical evidence
Studied in clinical trials for body-weight-reduction endpoints, including in combination with GLP-1 receptor agonists.
REDEFINE 1 (Phase 3a, NEJM 2025): Garvey et al., n=3,417, 68 weeks. Cagrilintide monotherapy: 11.8% mean weight loss vs 2.3% placebo. CagriSema: 20.4% vs semaglutide 14.9%. Trial-product estimand. REDEFINE 2 (Phase 3a, NEJM 2025): Davies et al., n=1,206, 68 weeks, T2D + BMI ≥27. CagriSema: 13.7% body-weight reduction and 1.91 percentage-point HbA1c reduction vs placebo. REDEFINE 4 (Phase 3, Feb 2026 readout): Open-label vs tirzepatide. CagriSema: 23.0% at 84 weeks vs tirzepatide 15 mg: 25.5%. Noninferiority endpoint not met. Lancet 2021 Phase 2 (monotherapy): Lau et al., n=706, 26 weeks. Cagrilintide 0.3-4.5 mg vs liraglutide 3 mg/day. 4.5 mg arm: 10.8% mean loss; 2.4 mg arm: 9.7%; liraglutide: 9.0%; placebo: 3.0%. Lancet 2021 Phase 1b (cagri + sema): Enebo et al., n=96, 20 weeks. Established additive effect of cagrilintide + semaglutide vs semaglutide alone (17.1% vs 9.8%). Lancet 2023 Phase 2 (T2D): Frias et al., n=92, 32 weeks. CagriSema: 15.6% weight loss and 2.2 pp HbA1c reduction. Cagrilintide alone: 8.1%. Semaglutide alone: 5.1%. Mechanism and pharmacology: Kruse et al. (J Med Chem 2021) characterized the C-20 fatty diacid spacer that extends the half-life. Fletcher et al. (Nature Communications 2025) mapped cagrilintide binding to amylin and calcitonin receptors structurally. Cardiovascular signal: Gabe et al. (Diabetes Obes Metab 2024) found no clinically relevant QTc prolongation. REDEFINE 3 cardiovascular outcomes trial is ongoing (~7,000 participants). Evidence Gap
- 01Cagrilintide is a long-acting, once-weekly amylin analog (an amylin/calcitonin receptor agonist) studied as an injectable clinical candidate (mechanistic / human study).
- 02In adults with overweight or obesity, cagrilintide as a single agent produced dose-dependent body-weight reduction in controlled trials (human study, Phase 2).
- 03In the Phase 3a REDEFINE program, the co-formulation with semaglutide (CagriSema) was associated with roughly 20% mean body-weight reduction at 68 weeks, versus about 11.5% for cagrilintide alone and about 14.9% for semaglutide alone (human study; reported 2025, New England Journal of Medicine).
- 04Gastrointestinal effects were the most commonly observed effects in research with the combination (human study observation).
- 05As of early-to-mid 2026, the developer indicated a regulatory filing for the semaglutide combination was planned; cagrilintide as a standalone agent remained investigational.
Evidence maturity varies by compound; much peptide research is preclinical (in vitro or animal-model). Where human data are limited, findings should be read as research observations, not clinical conclusions.
References
Literature references
Published research articles and sources related to Cagrilintide.
- 01Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1). New England Journal of Medicine (2025)et al. (2025)
- 02Davies MJ, Bajaj HS, Broholm C, et al. Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (REDEFINE 2). New England Journal of Medicine (2025)et al. (2025)
- 03Lau DCW, Erichsen L, Francisco AM, et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a Phase 2 trial. The Lancet (2021)et al. (2021)
- 04Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of cagrilintide with semaglutide for weight management: a Phase 1b trial. The Lancet (2021)et al. (2021)
- 05Frias JP, Deenadayalan S, Erichsen L, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with semaglutide 2.4 mg in type 2 diabetes: a Phase 2 trial. The Lancet (2023)et al. (2023)
- 06Kruse T, Hansen JL, Dahl K, et al. Development of Cagrilintide, a Long-Acting Amylin Analogue. Journal of Medicinal Chemistry (2021)et al. (2021)
- 07Fletcher MM, Belousoff MJ, Harikumar KG, et al. Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors. Nature Communications (2025)et al. (2025)
- 08Dehestani B, Stratford NR, le Roux CW. Amylin as a Future Obesity Treatment. Journal of Obesity & Metabolic Syndrome (2021)et al. (2021)
- 09Dutta D, Nagendra L, Harish BG, et al. Efficacy and Safety of Cagrilintide Alone and in Combination with Semaglutide (CagriSema) as Anti-Obesity Medications: A Systematic Review and Meta-Analysis. Indian Journal of Endocrinology and Metabolism (2024)et al. (2024)
- 10D'Ascanio AM, Mullally JA, Frishman WH. Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity. Cardiology in Review (2024)et al. (2024)
- 11Novo Nordisk (press release). CagriSema 2.4 mg / 2.4 mg demonstrated 22.7% mean weight reduction in adults with overweight or obesity in REDEFINE 1, published in NEJM. PR Newswire (2025)et al. (2025)
- 12Novo Nordisk (press release). Novo Nordisk files for FDA approval of CagriSema (December 18, 2025). PR Newswire (2025)et al. (2025)
- 13ClinicalTrials.gov. REDEFINE 1 (NCT05567796), REDEFINE 2 (NCT05394519), REDEFINE 3 (NCT05669755), REDEFINE 4 (NCT06131437), REDEFINE 11 (NCT07011667), REIMAGINE 2 (NCT06065540). U.S. National Library of Medicine (2026)et al. (2026)
Observed Effects
Observed effects in cited research
Observed Effects (From Clinical Trials)
- In the Lancet 2021 Phase 2 trial (n=706), at the highest 4.5 mg/week dose, 88% of participants reported at least one observed effect and 63% reported a GI-specific event. Across all doses, GI events were reported in 41-63% of cagrilintide groups versus 32% with placebo.
- Nausea47%
- Injection-site reactions43%
- Constipation21%
- Fatigue20%
- Allergic reactions (any)10%
- Vomiting8%
- Loose stools7%
- Headache7%
- Indigestion4%
- Incidence was lower at lower doses. Discontinuation due to adverse events was about 4% across all dose groups.
Gallstones
- One Phase 2 participant at 4.5 mg/week developed acute cholelithiasis (gallstones). Gallstone risk is a known class-level signal with rapid weight loss.
Anti-cagrilintide antibodies
- 46-73% of Phase 2 participants developed anti-cagrilintide antibodies by week 26. Phase 2 datasets did not show a clear effect on weight-loss efficacy or safety.
Cardiovascular safety
- A thorough QT study found no clinically relevant QTc prolongation, even at supratherapeutic doses. Long-term cardiovascular outcomes are still being evaluated in REDEFINE 3.
Injection-site reactions
- Mild redness or swelling at the injection site is common, especially during early titration. Rotating sites each week reduces local irritation.
Theoretical and Class-Level Risks
- These have not been confirmed in cagrilintide trials but are flagged because they appear in related amylin or GLP-1 class data: pancreatitis, gallbladder disease, severe hypoglycemia (mainly when combined with insulin or sulfonylureas), and acute kidney injury secondary to dehydration from severe nausea or vomiting.
Research Considerations
Research considerations
Research Use Only - not for human or veterinary therapeutic use. Investigational compound currently in clinical development; not approved for general use. Consult a licensed healthcare professional for any clinical decisions.
- Cagrilintide is investigational. It is studied in adults with overweight or obesity (BMI 27 or higher in REDEFINE 1) and in adults with type 2 diabetes (REDEFINE 2 and REIMAGINE 2). The published trials excluded several populations and conditions; that exclusion list is the most useful guide to who research planning should not include.
- Phase 3 REDEFINE/REIMAGINE protocols typically excluded participants with: Type 1 diabetes; history of pancreatitis; severe gastroparesis; pregnancy or breastfeeding; recent major cardiovascular events; active malignancy; severe renal or hepatic impairment; personal or family history of medullary thyroid carcinoma or MEN2 (a class-level GLP-1 caution that may extend to combination products).
- Because cagrilintide slows gastric emptying, it can change how oral medications are absorbed. Drugs with narrow therapeutic windows (warfarin, levothyroxine, oral contraceptives, certain seizure medications) deserve clinician oversight. Insulin and other glucose-lowering drugs may need adjustment to reduce hypoglycemia risk.
- Cagrilintide is not approved for individual self-administration. Anyone with metabolic, cardiac, GI, hepatic, or renal disease — or who is pregnant, breastfeeding, or planning pregnancy — should not consider it without licensed clinical care.
Factors noted in the research literature; not patient-specific medical advice.
Regulatory Status
Regulatory status
RUO
Comparisons
Comparisons
| Compound | Mechanism | Route | Status |
|---|---|---|---|
| Cagrilintidethis | A long-acting acylated amylin analog that activates central amylin (calcitonin-family) receptors to promote satiety and slow gastric emptying. | subcutaneous | Investigational / RUO |
| L-Carnitine | An amino acid derivative essential for transporting long-chain fatty acids into mitochondria for beta-oxidation and energy production. | subcutaneous | Investigational / RUO |
| Mazdutide | A long-acting dual agonist of GLP-1 and glucagon receptors, combining GLP-1 appetite/glycemic signaling with glucagon-mediated energy expenditure. | subcutaneous | Investigational / RUO |
| MOTS-C | A 16-amino-acid mitochondrial-derived peptide encoded in the 12S rRNA region of mtDNA that activates AMPK and influences nuclear stress-response gene expression, studied for metabolic homeostasis. | subcutaneous | Investigational / RUO |
| Retatrutide | An investigational triple-receptor agonist targeting GLP-1, GIP, and glucagon receptors, combining appetite regulation, insulinotropic activity, and increased energy expenditure. | subcutaneous | Investigational / RUO |
| Cartalax | A synthetic tripeptide bioregulator (Ala-Glu-Asp) studied for gene-regulatory activity in connective and cartilage tissue, with proposed anti-inflammatory and regenerative effects. | subcutaneous | Investigational / RUO |
| Cerebrolysin | A porcine brain-derived preparation of low-molecular-weight neuropeptides and free amino acids studied for neurotrophic activity supporting neuronal survival, synaptic plasticity, and modulation of neuroinflammation. | subcutaneous | Investigational / RUO |
Attributes shown for research comparison only; not a statement of efficacy or therapeutic equivalence.
FAQ
Frequently asked questions
It depends on the protocol format. CagriSema-style escalation starts at 0.25 mg per week with semaglutide and steps up every 4 weeks (0.5, 1.0, 1.7, 2.4 mg) over 16 weeks. Monotherapy protocols are commonly initiated at 0.6 mg per week and escalated to a maximum studied dose of 4.5 mg as tolerated.
Plasma half-life is about 159-195 hours, or roughly 6.6-8.1 days. Around the 2.4 mg dose, values near 184 hours have been reported in program summaries. This long half-life is what makes once-weekly dosing possible.
In REDEFINE 1 (NEJM 2025, n=3,417, 68 weeks), cagrilintide monotherapy at 2.4 mg produced 11.8% mean body-weight reduction versus 2.3% with placebo. CagriSema (cagrilintide + semaglutide) reached 20.4% in the same trial. In Phase 2, monotherapy at 4.5 mg/week reached 10.8% at 26 weeks. Individual response varies.
Reconstitute lyophilized cagrilintide with bacteriostatic water by injecting slowly down the inside wall of the vial, then gently swirl until the solution is clear. Do not shake. Common setups are a 5 mg vial with 2.0 mL BAC water (2.5 mg/mL) or a 10 mg vial with 3.0 mL (3.33 mg/mL). For exact unit conversion, use the PepPal calculator .
No. As of June 2026, cagrilintide is not FDA-approved in any form. Novo Nordisk filed an NDA for the CagriSema combination in December 2025, with an FDA decision anticipated in late 2026. Standalone cagrilintide (RENEW program) has no NDA filing yet.
The most common effects are gastrointestinal and dose-dependent. In the Lancet 2021 Phase 2 trial at 4.5 mg/week, nausea occurred in 47% of participants, injection-site reactions in 43%, constipation in 21%, and vomiting in 8%. Most events were mild to moderate and improved as the dose stabilized.
Cagrilintide acts on amylin and calcitonin receptors; semaglutide acts on GLP-1; tirzepatide acts on GLP-1 and GIP. Monotherapy weight-loss magnitude follows tirzepatide (22.5%) > semaglutide (~17%) > cagrilintide (11.8%). Cagrilintide's strongest use is in combination — CagriSema (with semaglutide) reached 20.4% in REDEFINE 1, but did not reach noninferiority versus tirzepatide 15 mg in REDEFINE 4.
Most research suppliers list 5 mg and 10 mg lyophilized vials. At 2.4 mg/week, a 5 mg vial covers about 2 weekly doses and a 10 mg vial covers about 4, before accounting for priming losses.
Volume depends on target concentration. Common reconstitutions are 5 mg + 2.0 mL (2.5 mg/mL), 10 mg + 3.0 mL (3.33 mg/mL), or 10 mg + 2.0 mL (5.0 mg/mL). Use the PepPal calculator for exact unit conversions at any concentration.
The highest monotherapy dose studied is 4.5 mg per week (Lancet 2021 Phase 2). The Phase 3 CagriSema program (REDEFINE 1, 2, REIMAGINE 2) capped cagrilintide at 2.4 mg per week. REDEFINE 11, initiated June 2025, is exploring extended duration and re-escalation strategies.
Refrigerate at 2-8 degrees Celsius (35.6-46.4 degrees Fahrenheit), protected from light, and use within 28-30 days. Do not freeze the reconstituted solution. Discard the vial if it becomes cloudy, discolored, or develops particles.
Because cagrilintide has a 7- to 8-day half-life, the published label-style guidance is to take a missed dose as soon as possible if the next scheduled dose is more than 3 days away, or to skip it if the next dose is closer than 3 days. Do not double-dose.
REDEFINE (obesity) and REIMAGINE (T2D) are the main Phase 3 programs, with REDEFINE 1, 2, and 4 already reported. REDEFINE 3 evaluates cardiovascular outcomes (~7,000 participants, event-driven). REDEFINE 11, initiated June 2025, tests extended treatment duration. RENEW is the planned monotherapy Phase 3 program.
Use the PepPal cagrilintide calculator for any vial size, BAC volume, or target dose conversion to U-100 syringe units.
Browse the PepPal supplier directory for current supplier listings, COA verification status, and discount codes.
Research-use notice
Research Use Only. This educational content and calculation support is intended for private research documentation. It does not provide medical advice, human-use directions, or claims of safety or effectiveness.