🐾 NexGard vs. Credelio vs. Simparica Trio

Confused by glossy ads, vague vet answers, or Reddit rabbit holes? You’re not alone. With NexGard®, Credelio®, and Simparica Trio® competing in your vet’s drawer, choosing the right parasite prevention feels more like a guessing game than a medical decision.

But here’s the truth: these aren’t just “flea and tick meds.” They’re prescription-only, pharmacologically distinct drugs—each with strengths, blind spots, and risks that matter deeply depending on your dog’s breed, age, lifestyle, and health vulnerabilities.


🧠 Key Takeaways: Real Answers at a Glance

Critical QuestionShort Answer
Which is best for tick protection?Simparica Trio – covers 6 species, widest scope.
Which treats tapeworms directly?Credelio Quattro – only one with praziquantel.
Which is safest for Collies/herding breeds?NexGard PLUS – no adverse signs even at 5× dose.
Which can be given without food?NexGard PLUS & Simparica Trio – flexible dosing.
Which works fastest on ticks?Credelio – kills some ticks within 8 hours.
Which works for the tiniest puppies?Simparica Trio – approved for 2.8 lb puppies.
Which is safest for beef-allergic dogs?Credelio Quattro – no actual beef proteins.
Do all have seizure risk?Yes – Isoxazoline class warning applies to all.

🐶 “Which Product Has the Best Tick Coverage?”

🏆 Simparica Trio wins hands down in tick spectrum.

It covers 6 tick species, including the aggressive Gulf Coast tick and invasive Asian longhorned tick—neither of which are on NexGard or Credelio’s labels.

📊 Tick Coverage Comparison:

Tick SpeciesNexGard PLUSCredelio QuattroSimparica Trio
Black-legged (Lyme carrier)
Lone Star Tick
Brown Dog Tick
American Dog Tick
Gulf Coast Tick 🏆
Asian Longhorned Tick 🏆

💡 Tip: Simparica Trio is ideal for dogs in the Southeast, Mid-Atlantic, and parts of the Northeast, where these newer ticks are emerging.


🪱 “What About Tapeworms? Do Any of These Treat Them?”

Only Credelio Quattro includes praziquantel—the gold standard tapeworm treatment.

ProductTapeworm TreatmentTapeworm Prevention Only
Credelio Quattro✔ Direct kill 🏆✔ Prevents via flea control
NexGard PLUS✔ (indirect via flea kill)
Simparica Trio✔ (indirect via flea kill)

🐕 Best pick for: dogs who hunt, scavenge, have fleas, or live where Echinococcus is a public health concern.


⚠️ “Is One Safer for Sensitive Breeds Like Collies?”

Yes – NexGard PLUS has the safest data for MDR1-deficient breeds (e.g., Collies, Aussies).

📊 MDR1-Deficient Collie Safety Study (at 5× overdose):

ProductSigns of NeurotoxicityRecovery Needed?Notes
NexGard PLUS❌ None 🏆Safest choice for herding dogs
Simparica Trio✔ Tremors, ataxia✔ Full recoveryOnly at extreme dose
Credelio Quattro❓ Not specifiedNo published MDR1 data yet

💡 Tip: When in doubt for Collies or Shelties, play it safe with NexGard PLUS.


🍖 “Which One Needs to Be Given With Food?”

Only Credelio and Credelio Quattro require food for proper absorption—bioavailability drops from 82% to 24% on an empty stomach!

ProductCan Be Given Without Food?🥣 Food Required
NexGard PLUS✔ Yes 🏆
Simparica Trio✔ Yes 🏆
Credelio Quattro❌ No✔ Yes

⚠️ Caution: Giving Credelio without food may result in treatment failure—especially dangerous in flea-infested homes.


🚀 “Which Kills Ticks the Fastest?”

Credelio leads in early tick kill rate (8–12 hours), according to European studies. Simparica and NexGard reach peak efficacy closer to 24–48 hours.

📊 Speed of Kill – Ticks:

Time to Significant KillNexGardSimparica TrioCredelio
4–8 Hours 🏆
24–48 Hours

🎯 Clinical context: For Lyme prevention, a kill before 24–36 hours is key. While all three meet this threshold, Credelio may offer quicker visible relief for dogs already infested.


🧬 “Are There Safety Differences in Side Effects?”

All three share a class-wide seizure risk warning (FDA mandated). Most side effects are GI-related and mild.

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📊 Reported Side Effects:

Side EffectNexGard PLUSSimparica TrioCredelio
Vomiting✔ 14.3%<1%<1%
Diarrhea✔ 13.2%1.0%1.0%
Seizures✔ Rare✔ Rare✔ Rare
Lethargy / Anorexia✔ Noted✔ Noted✔ Rare

💡 Pro Tip: For dogs with seizure history, consider non-isoxazoline options. No brand is completely risk-free within this class.


🐾 “What About Puppies? Who Can Get What—and When?”

Simparica Trio allows the smallest patients—approved for puppies as light as 2.8 lbs!

📊 Puppy Eligibility:

ProductMinimum AgeMinimum Weight
NexGard PLUS8 weeks4.0 lbs
Credelio Quattro8 weeks3.3 lbs
Simparica Trio8 weeks2.8 lbs 🏆

Perfect for: Toy breeds like Yorkies, Pomeranians, and Chihuahuas under 3.5 lbs.


🧪 “Can I Give These to Pregnant or Lactating Dogs?”

No clinical safety studies exist for any of these in pregnant or nursing dogs. Use of alternative parasite preventives is advised until safety is confirmed for these life stages.


🦴 “Which Tastes Better? Will My Dog Eat It?”

Manufacturer studies claim all three are highly palatable, but flavors differ.

ProductFlavor ProfileTexture
NexGard PLUSBeef-flavoredSoft chew 🦴
Simparica TrioPork liver-flavoredChewable tab
Credelio Quattro“Beef” (pork + soy)Tablet 💊

💡 Allergic to beef? Credelio is the only option with no beef proteins—despite the name.


🧭 Final Decision Guide: Best by Scenario

🐕 Scenario✅ Best Product📝 Why
Smallest puppy (<3.3 lbs)Simparica Trio 🏆Lowest weight minimum
Tapeworms or scavenging behaviorCredelio Quattro 🏆Only one with praziquantel
Tick-heavy region (Gulf Coast / Longhorned)Simparica Trio 🏆Only one with expanded tick label
MDR1-sensitive herding breedNexGard PLUS 🏆Safest margin in collie study
Picky eater / inconsistent appetiteNexGard PLUS or SimparicaCan be given without food
Known beef allergyCredelio Quattro 🏆Contains no beef protein

FAQs


💬 Comment: “My dog had a seizure after taking Simparica Trio. Should I be worried about using anything from this class again?”

Expert Reply:

You’re right to be cautious. Isoxazolines, including afoxolaner (NexGard), lotilaner (Credelio), and sarolaner (Simparica), share a class-wide FDA warning for potential neurologic effects—even in dogs with no prior seizure history. This includes muscle tremors, ataxia, and full seizures.

While adverse neurologic reactions are statistically rare, if your dog experienced a seizure temporally linked to Simparica Trio, it’s wise to consider a non-isoxazoline-based preventive going forward. Rechallenging with another isoxazoline may carry similar risks due to shared mechanisms at the GABA-gated chloride channels.

📊 Seizure Risk Context:

ProductFDA Seizure WarningNeurologic Events in TrialsSafe in Seizure Dogs?
NexGard PLUS✔ RequiredRare, <1%❌ Use caution
Simparica Trio✔ RequiredRare, transient in overdose❌ Use caution
Credelio Quattro✔ RequiredRare, <1% (head tremors)❌ Use caution

🐾 Tip: Discuss using topical or insect growth regulator (IGR) alternatives with your vet. Products like Revolution (selamectin) or Advantage Multi (imidacloprid + moxidectin) avoid the neurologic receptor targets that isoxazolines affect.


💬 Comment: “Do any of these protect against intestinal whipworms or giardia?”

Expert Reply:

None of the products in this comparison—NexGard PLUS, Simparica Trio, or Credelio Quattro—are labeled for whipworms (Trichuris vulpis) or Giardia lamblia, and none contain fenbendazole, febantel, or metronidazole, which are the cornerstone treatments for those organisms.

📌 Parasite Gaps in Coverage:

ParasiteNexGard PLUSSimparica TrioCredelio Quattro
Whipworms
Giardia lamblia
Roundworms/Hookworms
Tapeworms✔ (praziquantel)

💡 Tip: For dogs with confirmed whipworms, vets often co-administer Drontal Plus (praziquantel + febantel + pyrantel) or Panacur (fenbendazole) alongside monthly preventives. Giardia requires specific diagnostic testing (ELISA, fecal flotation with zinc sulfate) and treatment courses unrelated to these preventives.


💬 Comment: “How long after a dose can my dog swim or bathe? Does it affect the medication?”

Expert Reply:

Excellent question—and one that highlights a major advantage of oral isoxazolines over topical formulations.

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Since NexGard PLUS, Simparica Trio, and Credelio Quattro are systemic oral products, water exposure (bathing, swimming, rain) does NOT reduce their efficacy. The active ingredients are absorbed into your dog’s bloodstream, not applied to the coat.

🌊 Water & Efficacy Table:

ProductBathing/Swimming ImpactTime to Full AbsorptionSurface Application?
NexGard PLUS❌ None~2–6 hours❌ Oral chew
Simparica Trio❌ None~2–4 hours❌ Oral chew
Credelio Quattro❌ None (with food)~4 hours (fed only)❌ Oral chewable tab

💧 Caution: This doesn’t apply to topical products like Frontline or Advantage—those need up to 48 hours before water exposure.


💬 Comment: “Which one would help the most if my dog has Flea Allergy Dermatitis?”

Expert Reply:

If your dog has Flea Allergy Dermatitis (FAD)—an allergic hypersensitivity to flea saliva—then speed of kill becomes the top priority. Even a few bites can trigger weeks of inflammation, so killing fleas before they bite is ideal.

All three products—NexGard PLUS, Simparica Trio, and Credelio—kill adult fleas quickly. However, Credelio may have the slight edge in early kill window (within 4–8 hours), based on lab data.

📊 Flea Kill Speed for FAD Dogs:

ProductKills Fleas Within 4hFull Kill by 8hEffective for FAD Relief
NexGard PLUS✔ Some fleas✔ >99%
Simparica Trio✔ Partial✔ 100%
Credelio✔ >90% 🏆✔ 98–100%✔ Best Early Kill 🏆

🐕 Clinical tip: FAD patients often benefit from dual therapy—an oral flea adulticide plus an IGR spray or environmental treatment to prevent re-exposure from hatching pupae in the home.


💬 Comment: “What happens if I miss a dose by a few days?”

Expert Reply:

Missing a dose by even a few days can reopen the “window of vulnerability”—especially with heartworm disease, where immature larvae (L3, L4) must be killed before they mature.

💊 Isoxazoline efficacy persists longer than needed for fleas/ticks, but moxidectin (heartworm preventive) is time-sensitive, especially in high-risk mosquito areas.

📊 Missed Dose Risks:

ProductGrace Period for EctoparasitesHeartworm Protection Gap?Suggested Action
NexGard PLUS~5 days (fleas/ticks)✔ Risk of breakthroughTest in 6 months
Simparica Trio~5–7 days✔ YesResume + HW test
Credelio Quattro~3–5 days (only if food-compliant)✔ YesResume + HW test

🧬 Heartworm larvae development is slow (~51–70 days), but preventives only kill recent-stage larvae. If more than a week is missed, always notify your vet and plan a heartworm antigen + microfilaria test in 6 months.


💬 Comment: “Do any of these treat mites, like ear mites or mange?”

Expert Reply:

Great observation—this is one of the most under-discussed benefits of certain isoxazolines. Though U.S. labels don’t always include these claims, international data supports off-label or extrapolated use.

🪳 Mite Coverage Comparison (Based on Global Labeling & Studies):

Mite TypeNexGard PLUSSimparica TrioCredelio Quattro
Demodectic Mange (Demodex)✔ Intl data✔ Canada/AU✔ Europe only
Sarcoptic Mange (Scabies)✔ Intl data✔ Canada/AU❌ Not approved
Ear Mites (Otodectes)✔ Intl data✔ Intl data❌ Not approved

Clinical Tip: If your dog has mites, especially Demodex or Sarcoptes, your vet may still choose an isoxazoline even if not explicitly labeled in the U.S., because published studies demonstrate effectiveness.


💬 Comment: “Can I switch between these products month to month?”

Expert Reply:

Technically, yes—you can switch between isoxazoline-based preventives, but with strong caveats:

  1. Never overlap them (don’t give one before the previous has cleared).
  2. Ensure there is no lapse in heartworm coverage.
  3. Consider breed-specific sensitivities when switching between different macrocyclic lactones (e.g., moxidectin vs. ivermectin).

📅 Safe Switching Checklist:

SituationRecommended?Notes
Switching same class (NexGard → Simparica)✔ If spacedWait full 30 days; monitor for side effects
Switching different actives✔ With vet inputEspecially if new med adds praziquantel
Switching due to reaction❌ Without vetAdverse event needs full medical assessment

📌 Final tip: Always keep detailed records of when and which product was given. Switching requires dosing precision to avoid under- or overexposure.

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💬 Comment: “I’ve heard these drugs stay in a dog’s system for weeks—does that mean my dog is constantly medicated?”

Expert Reply:

Yes—but it’s more nuanced. Isoxazolines exhibit long half-lives, which is how they maintain consistent parasiticidal plasma levels over a 30-day dosing interval. However, this doesn’t mean your dog is “overmedicated”; it means the drug is steadily maintained at therapeutic, not excessive, levels to kill newly acquired parasites.

📈 Elimination Half-Life of Core Ingredients:

Drug (Product)Terminal Half-Life 🕒Functional Implication
Afoxolaner (NexGard)~14 daysSustains efficacy across 30 days
Lotilaner (Credelio)~28–30 days 🧬Allows precise monthly kill action
Sarolaner (Simparica)~11–13 daysBalanced duration with rapid kill speed

🧪 Note: These pharmacokinetics are intentionally designed to maintain efficacy against incoming parasite challenges—ticks, fleas, and in some cases, mites—throughout the month. The plasma levels taper gradually rather than stopping abruptly, which reduces the risk of “end-of-cycle” infestations.


💬 Comment: “Can I give these with vaccines or during illness?”

Expert Reply:

This is a critical clinical consideration. Isoxazoline-based preventives have not demonstrated immunosuppressive interactions when co-administered with vaccines, and in general, no adverse interactions have been reported with routine immunization protocols in healthy dogs.

However, during active illness or immune compromise, caution is warranted—particularly because:

  • Fever or gastrointestinal upset may alter drug absorption.
  • Neurologic symptoms might be exacerbated in sensitive animals, especially those with underlying seizure disorders.

📋 Administration Considerations with Vaccines or Illness:

ScenarioSafety Status ✅/⚠️Expert Tip 🧠
Routine Vaccinations✅ SafeAdminister on separate day if owner prefers monitoring
Mild GI Upset⚠️ Use cautionDelay 48 hrs post-symptom resolution
Neurologic symptoms❌ ContraindicatedAvoid all isoxazolines; use alternative parasiticides

🔎 Insight: If your dog is receiving immunosuppressants (e.g., prednisone) or undergoing chemotherapy, always consult your veterinarian—off-label caution may apply even when not reflected on product labels.


💬 Comment: “Is Credelio better tolerated in small dogs than NexGard or Simparica Trio?”

Expert Reply:

This perception comes largely from Credelio’s “gentle by design” marketing, which emphasizes its chiral purification—meaning it contains only the active stereoisomer of lotilaner, potentially reducing inert metabolic load. While this does make Credelio pharmacologically elegant, it doesn’t definitively make it clinically superior in tolerance for small dogs.

🔍 Key Data Points – Small Dog Tolerability (Based on Clinical Trials):

ProductVomiting % (Small Breed Trials)GI Upset NotedSpecial Notes
NexGard PLUS14.3%YesMild, transient
Simparica Trio<1%YesOne seizure noted at overdose
Credelio1.5–2%YesHead tremors in sensitive breeds

📏 Reality Check: All three products are formulated for safety in small dogs when dosed appropriately. However, Simparica Trio has the lowest approved weight threshold (2.8 lbs), making it the only legal choice for very small 8-week-old puppies.


💬 Comment: “How do I know which ticks are common in my area—and does it really matter?”

Expert Reply:

Absolutely—it matters more than most owners realize. Tick species vary significantly in geographic distribution, disease transmission potential, and product susceptibility. Selecting a product with the correct tick spectrum is essential in endemic or emerging tick zones.

🗺️ Region-Specific Tick Relevance in the U.S.:

Tick Species 🕷️Common Region 🧭Covered By…
Ixodes scapularis (Blacklegged)Northeast, MidwestAll products ✔
Amblyomma americanum (Lone Star)South, Central U.S.All products ✔
Rhipicephalus sanguineus (Brown Dog)Nationwide (indoor/outdoor)All products ✔
Amblyomma maculatum (Gulf Coast Tick)Gulf StatesSimparica Trio only
Haemaphysalis longicornis (Asian Longhorned)East Coast (expanding)Simparica Trio only

🧭 Takeaway: In New York or Pennsylvania, you might focus on Lyme coverage. In Texas or Florida, Gulf Coast tick protection becomes vital. Your vet is the best guide based on local parasite prevalence data.


💬 Comment: “What about drug resistance—can parasites become immune to these medications over time?”

Expert Reply:

Drug resistance is a valid concern, though the data for isoxazolines remains reassuringly stable. These drugs target GABA and glutamate-gated chloride channels, which are less mutation-prone than other parasite proteins. That said, resistance is a biological inevitability if misused.

📉 Resistance Risk Factors:

BehaviorResistance Impact 🛑Preventive Tip ✔️
Skipping dosesHigh riskMaintain strict monthly schedule
Underdosing (wrong weight)HighWeigh regularly and dose accurately
Off-label useUnknownAlways follow labeled indications
Using in high-load zones onlyModerateYear-round use discourages selection pressure

🧬 Flea and tick resistance to isoxazolines is not widely reported, but heartworm resistance to macrocyclic lactones (like moxidectin) is documented in parts of the Mississippi River Valley. This is another reason monthly compliance matters—it’s preventive medicine, not curative.


💬 Comment: “Can I use these products year-round, or should I stop in winter?”

Expert Reply:

We strongly advise year-round use, and here’s why:

  1. Indoor flea cycles continue even in cold months—egg-to-adult lifecycle is only 2–3 weeks in a heated home.
  2. Ticks survive mild winters under leaves and snow insulation. Some species, like I. scapularis, actively quest at temperatures as low as 39°F.
  3. Heartworm-carrying mosquitoes have been found indoors in winter, especially in Southern or temperate zones.

📆 Seasonal Risk vs. Year-Round Logic:

ParasiteActive in Winter? ❄️Year-Round Prevention Needed? ✅
Fleas✔ Indoor cycle✔ Yes
Ticks✔ Some species✔ Yes
Heartworm✔ In warm regions✔ Absolutely

💡 Clinical Tip: Stopping prevention during the off-season is a common cause of parasite resurgence, allergic flares, and even heartworm breakthrough cases. Most veterinarians now recommend 12-month use regardless of geography.


💬 Comment: “My dog refuses the chewable. Can I crush it and mix it into food?”

Expert Reply:

That depends on the product—and crushing is not uniformly safe or effective. These medications are formulated for consistent drug release and palatability, and altering them could interfere with both bioavailability and dosing accuracy.

Credelio and Credelio Quattro must be administered with food to ensure proper absorption (due to the fat-soluble nature of lotilaner), but they must remain whole to deliver the intended pharmacokinetic profile. Crushing can alter surface area exposure, potentially changing how the drug enters the bloodstream.

📦 Can I Crush It? Breakdown:

ProductCrushing Allowed? 🧪Notes
NexGard PLUS❌ Not advisedMay impair controlled absorption
Simparica Trio❌ Avoid crushingDrug dispersion may become erratic
Credelio Quattro❌ Do not crushCompromises food-dependent absorption

🧠 Alternative Strategy: Try hiding the chewable whole inside pill pockets, low-fat cheese, or canned food bites. For particularly suspicious dogs, your veterinarian may recommend compounding the medication into a flavored liquid by a licensed pharmacy—though this is off-label and needs prescription oversight.


💬 Comment: “Is there any reason to rotate between these preventives each year?”

Expert Reply:

The idea of rotating parasiticides annually—common in large animal medicine—is not supported for isoxazolines in small animal practice. These drugs maintain sustained efficacy with a low resistance profile when used consistently and correctly.

However, there are a few veterinary scenarios where rotation might be justified:

  1. Changing geographic parasite risks (e.g., moving from the Midwest to Gulf states with different tick burdens).
  2. Emerging side effects or reduced tolerability (e.g., GI upset, neurologic signs).
  3. Coverage Gaps: Switching to a product that includes praziquantel if tapeworms become a concern.

🔄 Rotation Decision Matrix:

Reason for RotationValid Justification? ✅Suggested Action
Annual efficacy boost❌ UnnecessaryStick to one product
New regional tick threats✔ YesRotate to broader-spectrum
Developing sensitivity✔ YesSwitch based on tolerance
Owner preference⚠️ Case-by-caseOnly under vet guidance

🧬 Bottom Line: If your current product is working and well-tolerated, there is no pharmacologic benefit to switching. Consistency helps maintain stable protection and owner compliance.


💬 Comment: “Can these meds cause kidney or liver damage over time?”

Expert Reply:

In clinical trials and long-term post-market surveillance, no evidence has emerged that any isoxazoline-based product causes cumulative hepatotoxicity or nephrotoxicity in healthy dogs. These medications are metabolized primarily via the liver (CYP enzymes) and eliminated slowly, but without accumulating beyond therapeutic thresholds.

That said, caution is warranted in:

  • Dogs with pre-existing hepatic insufficiency (e.g., portosystemic shunt, chronic hepatitis)
  • Patients with reduced renal function, though this is less relevant given hepatic clearance

🔬 Toxicity Evaluation Summary:

ProductHepatic Risk in Healthy DogsRenal Clearance ConcernMonitoring Needed?
NexGard PLUSNone knownMinimal renal excretionOnly if liver disease present
Simparica TrioNo long-term hepatic damagePrimarily hepatic routeBaseline liver enzymes in high-risk dogs
Credelio QuattroNo evidence of organ damageNo known renal impactMonitor if concurrent meds given

💡 Tip: For dogs on chronic NSAIDs, anticonvulsants, or steroids, ask your vet about periodic bloodwork to assess liver enzymes (ALT, ALP) and kidney markers (BUN, creatinine). The drugs themselves are low-risk, but drug-drug interactions can unmask underlying vulnerabilities.


💬 Comment: “How do I know if the flea product is working if I still see fleas after dosing?”

Expert Reply:

This is a frustrating but common concern, and often not a product failure. All three products begin killing adult fleas within 4–8 hours, with near-total kill by 12–24 hours. If fleas persist, consider the following culprits:

  1. Environmental re-infestation: Flea eggs can live in carpets, bedding, or cracks for months.
  2. Improper administration: Especially critical with Credelio, which requires food for efficacy.
  3. Inaccurate dosing: Underestimating weight or missing a dose window reduces plasma drug levels.

🪰 Flea Troubleshooting Guide:

Cause of Fleas After DosingFix 🛠️Product-Specific Concern?
New fleas emerging dailyTreat environment with IGRAll products (not environmental)
Given on empty stomachRepeat with food (if Credelio)Credelio Quattro
Skipped or late doseResume on scheduleAll
Flea resistance (rare)Rotate to topical adulticideRare but possible

🔬 Diagnostic Tip: Use a flea comb and white paper towel. Crush debris and add water—if it turns reddish-brown, you’re seeing flea dirt (digested blood), confirming active infestation.


💬 Comment: “My dog eats raw food—will that interfere with these meds?”

Expert Reply:

Raw food diets do not inherently interfere with the pharmacodynamics of isoxazoline-based products. However, raw diets are often high in fat, which could enhance absorption of fat-soluble drugs like lotilaner (Credelio). In fact, this is beneficial for products requiring food-based administration.

Caveats include:

  • Unpredictable digestion rates can lead to variable Tmax values—the time it takes for the drug to reach maximum concentration.
  • GI flora alterations from raw food may hypothetically affect metabolism, but this is not clinically proven.

🥩 Raw Diet Interaction Chart:

Drug (Product)Impact of High-Fat MealRaw Diet Caution?
Afoxolaner (NexGard)Minimal❌ Not impacted
Lotilaner (Credelio)Boosts absorption 👍✔ Improved efficacy
Sarolaner (Simparica)Neutral❌ Not impacted

⚠️ Final Note: Raw diets increase parasite risk—including tapeworms and protozoa. If feeding raw, strongly consider Credelio Quattro for tapeworm protection via praziquantel.

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