Varenzin-CA1 is indicated for the control of nonregenerative anemia associated with chronic kidney disease (CKD) in cats.

Varenzin-CA1 is a Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, stimulating a cat’s body to produce its own erythropoietin (EPO). Varenzin-CA1 is the FIRST and ONLY FDA conditionally approved option for the treatment of CKD-related anemia in cats.

HIF is a complex of proteins that switches on the activity of genes needed to make erythropoietin (EPO) and other proteins that help cells adjust to low-oxygen conditions.³

HIF-PH is an oxygen-sensitive enzyme that degrades HIF under normal oxygen conditions⁴, thus decreasing the production of erythropoietin (EPO).

The main cause of anemia in CKD patients is the lack of erythropoietin (EPO), a renal hormone that controls the bone marrow’s production of red blood cells.²

In these cats, reduced metabolic activity of the failing kidneys leads to a relative hyperoxia therefore reducing EPO production despite a preserved EPO mechanism. Production of EPO progressively decreases as the kidney is failing due to the continuous loss of functioning renal EPO-producing cells caused by:²

• Fibrosis
• Uremic substances causing oxidative stress shortening red blood cell (RBC) lifespan
• Chronic presence of inflammatory cytokines impairing hypoxia-inducible factor (HIF)
• Impaired iron mobilization

Gastrointestinal hemorrhage and other sources of blood loss can also contribute to anemia.

It is estimated that 15-30% of geriatric cats will develop CKD, and 30-65% of these cats will develop anemia as their renal disease progresses.²

In addition, incidence of anemia increases with IRIS Stage:⁵

• Stage 2: 4.8%
• Stage 3: 17.7%
• Stage 4: 53.3%

Anemia affects the body negatively in a number of ways (weakness, lethargy, inappetence) leading to an overall decrease in quality of life.²

Anemia triggers numerous adaptive tissue response mechanisms due to tissue hypoxia, including release of norepinephrine, renin, angiotensin II, and aldosterone, all which can lead to sympathetic nervous system response, increased heart contractility and rate, and increased blood pressure.²

As anemia becomes more severe, cats may also develop left heart enlargement secondarily to hemodynamic compensation, and become prone to congestive heart failure, especially if receiving intravenous fluid therapy.²

Cats with CKD have reduced survival times once anemia occurs.⁶

• Approximately 3 months at onset of anemia
• Compared to approximately 2 years median survival time for feline CKD overall

Varenzin-CA1 is a 25mg/mL oral suspension.

The 27 mL bottle is designed to last a cat for the full 28 days of treatment.

Varenzin-CA1 is flavored with fish oil mixed into the primary carrier of sunflower oil.

In a palatability study, all cats offered the oily suspension of Varenzin-CA1 showed an interest in voluntary intake of Varenzin when offered in a bowl, and daily doses of up to 5 mg/kg was well tolerated for six consecutive doses.⁷

The dosage of Varenzin-CA1 is 2.3 mg/lb (5 mg/kg) body weight administered orally once daily for up to 28 consecutive days, rounded up to the nearest 0.1 mL using the dosing syringe provided in the package. As a conditionally approved product, Varenzin-CA1 should not be used in an off-label manner.

Cats greater than 13.2 pounds body weight should be treated with a dose of 2.3 mg/pound body weight rounded up to the nearest 0.1 mL.

Yes. Varenzin-CA1 may be given with or without food.

Elanco has not conducted any studies where Varenzin-CA1 was added to food and fed to a cat. Per the label, the product should be administered with the syringe directly into the cat’s mouth.

Varenzin-CA1 should be stored at room temperature (68°-77°F).  Shelf life is 24 months.

A stability study shows that the drug product is stable for at least 28 days after opening of the container and stored at label storage conditions and temperatures up to 30°C (86°F).⁷

Varenzin-CA1 can be started after a cat has been diagnosed with nonregenerative anemia associated with chronic kidney disease and the hematocrit or packed cell volume is below the reference range.

Varenzin-CA1 is labeled to be administered orally once daily for up to 28 consecutive days. Treatment may be repeated after a minimum 7-day pause. Minimal accumulation of molidustat is expected based on the plasma pharmacokinetic profile. Therefore, it is not necessary to taper the dose prior to discontinuation.

Per the label, a minimum 7-day pause is required after administering Varenzin-CA1 daily for up to 28 consecutive days. Treated cats should initially have their hematocrit (HCT) or packed cell volume (PCV) levels monitored weekly beginning about the 14^th day of the 28-day treatment cycle. Discontinue Varenzin-CA1 if the HCT or PCV exceeds the upper limit of the reference range.

After treatment cessation, the hematocrit (HCT) or packed cell volume (PCV) level should be periodically checked (every 7-28 days). When the HCT or PCV level declines below the lower limit of the reference range and at least 7 days have passed since the previous treatment, a new treatment cycle may be started. The interval between treatment cycles will vary between cats and may change over time for an individual cat but should be at least 7 days.

Per the label, Varenzin-CA1 is to be administered orally once daily for up to 28 consecutive days. Treatment may be repeated after a 7-day pause. As a conditionally approved product, Varenzin-CA1 should not be used in an off-label manner.

Per the label, Varenzin-CA1 is to be administered orally once daily for up to 28 consecutive days. Treatment may be repeated after a 7-day pause. As a conditionally approved product, Varenzin-CA1 should not be used in an off-label manner. Giving Varenzin-CA1 less frequently has not been studied and could potentially result in reduced efficacy.

Per the label, Varenzin-CA1 is to be administered orally once daily for up to 28 consecutive days. Treatment may be repeated after a minimum 7-day pause. It can be continued in this fashion as long as the hematocrit (HCT) or packed cell volume (PCV) does not exceed the upper limit of the reference range.

Treated cats should initially have their HCT or PCV levels monitored weekly beginning about the 14^th day of the 28-day treatment cycle to ensure HCT or PCV does not exceed the upper limit of the reference range. Discontinue Varenzin-CA1 if HCT or PCV exceeds the upper limit of the reference range.

After treatment cessation, the HCT level should be periodically checked (for example, weekly, every 2 weeks or monthly). When the HCT or PCV level declines below the lower limit of the reference range, a new treatment cycle should be started.

Additional monitoring should be based on concomitant medical conditions and IRIS staging.

In a field efficacy study, the molidustat treatment group average weekly responses ranged from increases of 1.65% to 3.91%, as compared to the average baseline, starting as early as SD (Study Day) 7. Compared to the control group, the HCT and packed cell volume (PCV) were significantly greater on SD 21.⁷

If a cat does not respond to treatment after 3 weeks, it is recommended to re-examine the animal for any other underlying conditions that may contribute to anemia, such as:

• Iron deficiency
• Inflammatory diseases
• Blood loss (GI bleeding)

In the molidustat field efficacy study, 50% (7/14) of the cats in the treatment group were considered successes compared to only 16.7% of the control cats (1/6).¹ In the continuation phase, 75% (6/8) of the cats were considered successes on SD 56 and 62.5% (5/8) of the cats were considered successes.

In a study evaluating darbepoetin in cats with anemia of chronic kidney disease, 56% (14/25) responded with a PCV ≥ 25% by 3 weeks (average) and persisted ≥ 8 weeks.⁸

Vomiting was the most frequently reported adverse event in preliminary studies. Increases in systolic blood pressure and mild transient increases in serum potassium were also observed.

One cat in the molidustat group presented on SD (Study Day) 28 in lateral recumbency with a cold front leg from suspected thromboembolism and was euthanized. A necropsy was not performed.

In a separate study, one cat had a seizure associated with severe uremia, severe anemia, and dehydration. A second cat, which had a history of seizures about 1 year prior, had a seizure and severe hypertension.

If the cat vomits after consuming any portion of the dose, the cat should not be re-dosed and should be considered as dosed for the day.

Polycythemia may result from use of Varenzin-CA1. When starting Varenzin-CA1, cats should have their hematocrit (HCT) or packed cell volume (PCV) levels monitored regularly during the treatment cycle to ensure HCT or PCV does not exceed the upper limit of the reference range.

Varenzin-CA1 has also been associated with thromboembolic disease. In a field efficacy study, one cat in the molidustat group presented in lateral recumbency with a cold front leg from a suspected thromboembolism after 28 days of treatment.

A single overdose of Varenzin-CA1 is unlikely to cause significant side effects, other than possible vomiting, decreased appetite, or lethargy.⁷ Treatment would be symptomatic and supportive.

There is no age restriction on the label. However, the label does state that the safe use of Varenzin-CA1 has not been evaluated in cats less than 1 year of age.

Varenzin-CA1 is indicated for the control of nonregenerative anemia associated with chronic kidney disease (CKD) in cats. As a conditionally approved product, Varenzin-CA1 should not be used in an off-label manner.

Per the label, the syringe included with the Varenzin-CA1 product cannot be used to accurately dose cats weighing under 3.4 pounds. As a conditionally approved product, Varenzin-CA1 should not be used in an off-label manner.

The use of iron supplementation was not evaluated in our studies, as molidustat is not dependent on iron to be efficacious. However, if iron deficiency is present, iron supplements can be administered.

Phosphate binders or other products containing multivalent cations, such as calcium, iron, magnesium, or aluminum have been shown to chelate with other HIF-PH inhibitors. Based on information in humans, consider staggered administration of Varenzin-CA1 and phosphate binders and iron supplements at least 1 hour apart, if possible, to prevent potentially decreasing absorption of molidustat.

The use of Varenzin-CA1 administered concurrently with other erythropoiesis-stimulating agents (ESAs), including recombinant human erythropoietin (rHuEPO) drugs, has not been studied. The decision regarding whether or not to transition a patient from other ESAs to Varenzin-CA1 is ultimately the responsibility of the prescribing veterinarian.