موليدوستات

Conditionally approved for the control of nonregenerative anemia associated with chronic kidney disease (CDK) in cats.

Varenzin™-CA1

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

FDA application 141-571

Mechanism of Action Varenzin-CA1 (molidustat oral suspension) is a competitive and reversible inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH). The inhibition of HIF-PH induces a dose-dependent increase of endogenous erythropoietin (EPO) by stabilizing HIF, resulting in increased erythropoiesis (red blood cell production). Pharmacokinetics The pharmacokinetic parameters of Varenzin-CA1 after a single oral dose of 2.5, 5, and 10 mg/kg bw and intravenous dose of 5 mg/kg bw were evaluated in a laboratory study in which 8 healthy, young adult cats (4 neutered males, 4 spayed females) received Varenzin-CA1 orally or molidustat sodium aqueous suspension intravenously, utilizing a crossover study design. Following oral administration, molidustat was rapidly absorbed. Table 2: Mean (± standard deviation) pharmacokinetic parameters of molidustat following a single oral or intravenous dose of 5 mg/kg in cats: † Median and range are reported for Tmax instead of arithmetic mean and standard deviation †† C0 back-extrapolated concentration at time 0 by a log-linear regression of first 2 data points following intravenous administration Cmax: Maximum observed plasma concentration Tmax: Time to maximum observed plasma concentration AUClast: Area under the plasma concentration versus time curve from time of dosing to the last quantifiable concentration AUCinf: Area under the plasma concentration versus time curve from time of dosing extrapolated to infinity T1/2: Terminal elimination half-life Route Oral Intravenous Tmax † (hour) 1 (0.67 – 1.5) Not Applicable Cmax (µg/mL) 3.86 ± 0.495 26.0 ± 8.42†† AUClast (hour*µg/mL) 13.0 ± 2.98 16.5 ± 2.97 AUCinf (hour*µg/mL) 13.1 ± 2.99 16.6 ± 3.01 T1/2 (hour) 4.68 ± 0.661 6.28 ± 4.43 The pharmacokinetic parameters of molidustat after 6 daily oral doses of 5 mg/kg bw were evaluated in a second laboratory study using 8 healthy, young adult cats (4 neutered males, 4 spayed females). Minimal accumulation of molidustat in the plasma pharmacokinetic profile was observed in the study.

FDA application 141-571

Varenzin-CA1 should not be administered to cats with known hypersensitivity to molidustat or to any of the inactive ingredients. Varenzin-CA1 should not be administered to cats that are pregnant, lactating, or intended for breeding. In an embryo-fetal-developmental toxicity study in rats, an increase incidence of ocular malformations such as flat eye rudiments and microphthalmia were observed at doses of 30 mg/kg bw per day. These effects may be due to an increase in oxygen availability, caused by molidustat-induced polycythemia. Localized hypoxia is an important factor in normal eye development. Developmental toxicity studies have not been conducted in cats. Available animal data have shown excretion of other HIF-PH inhibitors into milk. It is unknown whether molidustat is excreted into the milk of lactating cats.

FDA application 141-571

User Safety Warnings Not for use in humans. Keep this drug, including used syringes, out of reach of children. Wash hands immediately after use and/or spillage. In case of accidental ingestion, seek medical advice immediately and show the package leaflet or the label to the physician. Symptoms of exposure to molidustat may include the following: gastrointestinal effects (nausea, vomiting, diarrhea), blood and clotting effects (increases in reticulocytes, erythropoietin, and hemoglobin), dizziness, fainting, hypertension, changes in cardiac output and cardiac index, and increases in heart rate. Symptoms may not occur immediately; therefore, the exposed individual should be monitored. People with known hypersensitivity to molidustat sodium should avoid direct contact with this product and should administer the product with caution. Women who are pregnant or may become pregnant should administer the product with caution. Molidustat administered orally to pregnant rats during the period of organogenesis was associated with adverse fetal outcomes (see CONTRAINDICATIONS ). Do not eat, drink, or smoke while handling this product. Animal Safety Warnings Keep Varenzin-CA1 in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

FDA application 141-571

The safety of Varenzin-CA1 was evaluated in a masked, controlled 28-day field study to evaluate the effectiveness of molidustat oral suspension (not commercial formulation) for the control of nonregenerative anemia associated with CKD in cats (see REASONABLE EXPECTATION OF EFFECTIVENESS ). Enrollment included 21 cats; 15 cats were treated with Varenzin-CA1, and 6 cats were administered a vehicle control. Eight of these cats were subsequently enrolled in an extended open-label safety study for up to 8 additional weeks. Cats were dosed daily for 28 days. Vomiting was the most frequently reported adverse event, observed in 6/15 (40%) cats in the molidustat group and no cats in the control group. Increases in systolic blood pressure and mild transient increases in serum potassium were also observed. The most serious adverse event was a cat in the molidustat group that presented, after 28 days of treatment, in lateral recumbency with a cold front leg from a suspected thromboembolism and was euthanized. The safety of Varenzin-CA1 was evaluated in an interim analysis of data collected in an open label safety phase of an ongoing clinical field effectiveness and safety study. Varenzin-CA1 was administered for 28 consecutive days, followed by a treatment pause of at least 7 days, then treatment was repeated for up to 4 treatment cycles. The study evaluated 55 client-owned cats with nonregenerative anemia (PCV < 28%) secondary to CKD that had received at least one dose of Varenzin-CA1 at 5 mg/kg bw in the safety phase. Cats had a mean age of 13 years (range 5.2 to 23.4) and initial body weights between 2.3 to 5.9 kilograms. At baseline just prior to enrollment into the study, 31%, 47%, and 22% of cats were in International Renal Interest Society (IRIS) Stage 2, 3, and 4 CKD, respectively (to learn more about IRIS staging, visit http://www.iris-kidney.com/index.html). Vomiting was the most frequently reported adverse event, either alone or with other events, and was reported at least once in 29/55 (52.7%) of the cats in the study. Vomiting was more frequent on treatment days than during treatment pause. Two cats had seizures during the study. One cat had a seizure associated with severe uremia, severe anemia, and dehydration. One cat, which had a history of a seizure about 1 year prior, had a seizure during the study and severe hypertension. Nineteen cats died or were euthanized before completion of the safety phase of the study due to worsening CKD or declining quality of life, and one cat was euthanized due to an abdominal mass.

FDA application 141-571

Administer orally at a dosage of 5 mg/kg of body weight (2.3 mg/lb) daily for up to 28 consecutive days. Treatment may be repeated after a minimum 7-day pause.

Oral

Varenzin™-CA1

Shake well before use. The dosage of Varenzin-CA1 is 2.3 mg/lb (5 mg/kg) body weight (bw) administered orally once daily for up to 28 consecutive days. Treatment may be repeated after a minimum 7-day pause (see Monitoring and Repeating Treatment ). Varenzin-CA1 should be administered using the dosing syringe provided in the package. The dosing syringe is marked in increments of 0.1 mL. The dose should be rounded up to the nearest 0.1 mL. Dosing Information To ensure the correct dose is administered, body weight should be determined prior to starting each treatment cycle. Table 1. Dosing Chart Weight Range in pounds (lb) Volume of Varenzin-CA1 (mL) 3.4 to 4.4 0.4 4.5 to 5.5 0.5 5.6 to 6.6 0.6 6.7 to 7.7 0.7 7.8 to 8.8 0.8 8.9 to 9.9 0.9 10 to 11 1 11.1 to 12.1 1.1 12.2 to 13.2 1.2 Note: The syringe included with the Varenzin-CA1 product cannot be used to accurately dose cats weighing under 3.4 pounds. Cats greater than 13.2 lb bw should be treated with a dose of 2.3 mg/lb bw rounded up to the nearest 0.1 mL. Administration Shake well before use. Remove screw cap. Use the enclosed syringe for each treatment. Place the syringe nozzle firmly into the opening of the bottle. Turn the bottle upside down and withdraw the necessary volume. Turn the bottle back into an upright position before removing the syringe. The product should be administered with the syringe into the cat’s mouth. See illustrations 1 through 4 below for administration steps: After administration, close bottle tightly with cap and store syringe in the carton together with the product. Do not disassemble or wash the syringe. The product should be given once daily for up to 28 consecutive days. 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. Monitoring and Repeating Treatment Treated cats should initially have their hematocrit (HCT) or packed cell volume (PCV) levels monitored weekly beginning about the 14th 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 hematocrit 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. 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. If a cat does not respond to treatment after 3 weeks (see REASONABLE EXPECTATION OF EFFECTIVENESS ), it is recommended to re-examine the animal for any other underlying condition that may contribute to anemia, such as iron deficiency, inflammatory diseases or blood loss. It is advised to treat the underlying condition before restarting treatment with Varenzin-CA1.

ORAL

FDA application 141-571