Levetiracetam

Warnings and Precautions (5.5) 3/2024 Warnings and Precautions (5.5) 3/2024

1 INDICATIONS AND USAGE Levetiracetam Injection is indicated for the treatment of partial-onset seizures in patients 1 month of age and older ( 1.1 ) Levetiracetam Injection is indicated for adjunctive therapy for the treatment of: Myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy ( 1.2 ) Primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy ( 1.3 ) Levetiracetam Injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible ( 1.4 ) 1.1 Partial-Onset Seizures Levetiracetam Injection is indicated for the treatment of partial-onset seizures in patients 1 month of age and older. 1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam Injection is indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy. 1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam Injection is indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy. 1.4 Limitations of Use Levetiracetam Injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

1.1 Partial-Onset Seizures Levetiracetam Injection is indicated for the treatment of partial-onset seizures in patients 1 month of age and older.

1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam Injection is indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy.

1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam Injection is indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy.

2 DOSAGE AND ADMINISTRATION For intravenous infusion only ( 2.1 ) Do not dilute prior to its use ( 2.1 ) Administer dose-specific container intravenously over 15-minutes ( 2.1 ) Initial Exposure to Levetiracetam Partial-Onset Seizures: Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to a maximum recommended dose of 1,500 mg twice daily (2.2). Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy: Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to the recommended dose of 1,500 mg twice daily (2.2). Primary Generalized Tonic-Clonic Seizures: Initial dose is 500 mg twice daily. Increase by 500 mg twice daily every 2 weeks to the recommended dose of 1,500 mg twice daily (2.2). Switching from or to oral Levetiracetam: The total daily dosage/frequency of levetiracetam injection should be equivalent to those of oral levetiracetam (2.3, 2.4). Renal Impairment: Dose adjustment necessary based on creatinine clearance ( 2.5 ). 2.1 General Information – Administration Levetiracetam in Sodium Chloride Injection is for intravenous infusion only. It is available in the following concentrations: three single-dose 100 mL fill containers, each containing a different total dosage of levetiracetam (500 mg [5 mg/mL], 1,000 mg [10 mg/mL], or 1,500 mg [15 mg/mL]). A single-dose container should be administered intravenously over a 15-minute IV infusion period. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Levetiracetam in Sodium Chloride Injection should not be further diluted prior to use. Any unused portion of the Levetiracetam in Sodium Chloride Injection contents should be discarded. 2.2 Initial Exposure to Levetiracetam Levetiracetam can be initiated with either intravenous or oral administration. Partial-Onset Seizures In clinical trials of oral levetiracetam, daily doses of 1,000 mg, 2,000 mg, and 3,000 mg, given as twice-daily dosing, were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose [see Clinical Studies (14.1) ], a consistent increase in response with increased dose has not been shown. Treatment should be initiated with a daily dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg. Doses greater than 3,000 mg/day have been used in open-label studies with levetiracetam tablets for periods of 6 months and longer. There is no evidence that doses greater than 3,000 mg/day confer additional benefit. Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Treatment should be initiated with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg. The effectiveness of doses lower than 3,000 mg/day has not been studied. Primary Generalized Tonic-Clonic Seizures Treatment should be initiated with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied. 2.3 Switching to Intravenous Dosing When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam should be equivalent to the total daily dosage and frequency of oral levetiracetam. 2.4 Switching to Oral Dosing At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration. 2.5 Adult Patients with Impaired Renal Function Levetiracetam dosing must be individualized according to the patient's renal function status. Recommende …

3 DOSAGE FORMS AND STRENGTHS Injection: Levetiracetam in Sodium Chloride Injection is a clear, colorless solution packaged in a single-dose container and available in three strengths: 500 mg/100 mL (5 mg/mL): 500 mg levetiracetam in 0.82% sodium chloride injection 1,000 mg/100 mL (10 mg/mL): 1,000 mg levetiracetam in 0.75% sodium chloride injection 1,500 mg/100 mL (15 mg/mL): 1,500 mg levetiracetam in 0.54% sodium chloride injection Levetiracetam in Sodium Chloride Injection in single-dose containers: Levetiracetam in 0.82% sodium chloride injection (500 mg/100 mL) (5 mg/mL) ( 3 ) Levetiracetam in 0.75% sodium chloride injection (1,000 mg/100 mL) (10 mg/mL) ( 3 ) Levetiracetam in 0.54% sodium chloride injection (1,500 mg/100 mL) (15 mg/mL) ( 3 )

4 CONTRAINDICATIONS Levetiracetam in Sodium Chloride Injection is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions ( 5.3 )] . • Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in more details in other sections of labeling: • Psychiatric Reactions [see Warnings and Precautions ( 5.1 )] • Somnolence and Fatigue [see Warnings and Precautions ( 5.2 )] • Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.3 )] • Serious Dermatological Reactions [see Warnings and Precautions ( 5.4 )] • Coordination Difficulties [see Warnings and Precautions ( 5.5 )] • Withdrawal Seizures [see Warnings and Precautions ( 5.6 )] • Hematologic Abnormalities [see Warnings and Precautions ( 5.7 )] • Seizure Control During Pregnancy [see Warnings and Precautions ( 5.8 )] • Most common adverse reactions (incidence in levetiracetam-treated patients is ≥ 5% more than in placebo-treated patients) include: somnolence, asthenia, infection, and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reactions that result from levetiracetam injection use include all of those reported for levetiracetam tablets and oral solution. Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent C max , C min , and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15-minute infusion. Partial-Onset Seizures In controlled clinical studies using levetiracetam tablets in adults with partial-onset seizures [see Clinical Studies ( 14.1 )] , the most common adverse reactions in adult patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection and dizziness. Of the most common adverse reactions in adults experiencing partial-onset seizures, asthenia, somnolence and dizziness occurred predominantly during the first 4 weeks of treatment with levetiracetam. Table 2 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam tablets in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 2: Adverse Reactions* In Placebo-Controlled, Adjunctive Studies In Adults Experiencing Partial-Onset Seizures * Adverse reactions occurred in at least 1% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients Adverse Reaction Levetiracetam (N=769) % Placebo (N=439) % Asthenia 15 9 Somnolence 15 8 Headache 14 13 Infection 13 8 Dizziness 9 4 Pain 7 6 Pharyngitis 6 4 Depression 4 2 Nervousness 4 2 Rhinitis 4 3 Anorexia 3 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Cough Increased 2 1 Diplopia 2 1 Emotional Lability 2 0 Hostility 2 1 Paresthesia 2 1 Sinusitis 2 1 In controlled adult clinical studies using levetiracetam tablets, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 3 lists the most common (>1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients. Table 3: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Placebo- Controlled Studies in Adults Experiencing Partial-Onset Seizures Adverse Reaction Levetiracetam (N=769) % Placebo (N=439) % Somnolence 4 2 Dizziness 1 0 Myoclonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures …

Drug Interactions In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above C max levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients. Phenytoin Levetiracetam (3,000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin. Valproate Levetiracetam (1,500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057. Other Antiepileptic Drugs Potential drug interactions between levetiracetam and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam. Oral Contraceptives Levetiracetam (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam. Digoxin Levetiracetam (1,000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam. Warfarin Levetiracetam (1,000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam. Probenecid Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1,000 mg twice daily. C ss max of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057. The effect of levetiracetam on probenecid was not studied.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Plasma levels of levetiracetam may be decreased; monitor closely during pregnancy. Based on animal data, may cause fetal harm ( 5.9 , 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including Levetiracetam Injection, during pregnancy. Encourage women who are taking Levetiracetam Injection during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Prolonged experience with Levetiracetam Injection in pregnant women has not identified a drug- associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries, and reflects experience over two decades [see Human Data]. In animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see Animal Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Levetiracetam blood levels may decrease during pregnancy [see Warnings and Precautions ( 5.10 )]. Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester. Dose adjustments may be necessary to maintain clinical response. Data Human Data While available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. Animal Data When levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a body surface area (mg/m2) basis. Oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the MRHD on a mg/m2 basis. Oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on pre-and postnatal development in rats (70 mg/kg/day) is less than the MRHD on a mg/m2 basis. Oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m2 basi …

12.1 Mechanism of Action The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

11 DESCRIPTION Levetiracetam in Sodium Chloride Injection is an antiepileptic drug available as a clear, colorless, sterile solution for intravenous administration. The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C 8 H 14 N 2 O 2 and its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula: Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent.) Levetiracetam in Sodium Chloride Injection is a clear, colorless, sterile solution that is available in a single-dose dual port container. This container closure is not made with natural rubber latex, PVC or DEHP. 500 mg/100 mL: One 100 mL fill container contains 500 mg of levetiracetam (5 mg/mL), water for injection, 820 mg sodium chloride, 5.5 mg of glacial acetic acid and buffered at approximately pH 5.5 with glacial acetic acid and 164 mg sodium acetate trihydrate. 1,000 mg /100 mL : One 100 mL fill container contains 1,000 mg of levetiracetam (10 mg/mL), water for injection, 750 mg sodium chloride, 6.5 mg of glacial acetic acid and buffered at approximately pH 5.5 with glacial acetic acid and 164 mg sodium acetate trihydrate. 1,500 mg /100 mL : One 100 mL fill container contains 1,500 mg of levetiracetam (15 mg/mL), water for injection, 540 mg sodium chloride, 7.5 mg of glacial acetic acid and buffered at approximately pH 5.5 with glacial acetic acid and 164 mg sodium acetate trihydrate. The plastic container is a copolymer of ethylene and propylene formulated and developed for parenteral drugs. The copolymer contains no plasticizers. The safety of the plastic container has been confirmed by biological evaluation procedures. The material passes Class Vl testing as specified in the U.S. Pharmacopeia for Biological Tests — Plastic Containers. The container/solution unit is a closed system and is not dependent upon entry of external air during administration. The container has two ports, one is for the intravenous administration set and the other is a medication addition. Each is covered by a tamperproof barrier. Refer to the DIRECTIONS FOR USE of the container to properly identify the ports. No vapor barrier is necessary. Structural Formula

10 OVERDOSAGE 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of oral levetiracetam received in the clinical development program was 6,000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses in postmarketing use. 10.2 Management of Overdose There is no specific antidote for overdose with levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with levetiracetam. 10.3 Hemodialysis Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of oral levetiracetam received in the clinical development program was 6,000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses in postmarketing use.

10.2 Management of Overdose There is no specific antidote for overdose with levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with levetiracetam.

10.3 Hemodialysis Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Levetiracetam in Sodium Chloride Injection is a clear, colorless, sterile solution that is available in a single-dose 100 mL dual port bag with an over wrap. The container closure is not made with natural rubber latex. It is available in the following presentations: Product Code Unit of Sale Strength Each 455000 65219-042-71 Package of 24 500 mg in 100 mL (5 mg per mL) 65219-042-21 100 mL single-dose bag 455100 65219-044-71 Package of 24 1,000 mg in 100 mL (10 mg per mL) 65219-044-21 100 mL single-dose bag 455200 65219-046-71 Package of 24 1,500 mg in 100 mL (15 mg per mL) 65219-046-21 100 mL single-dose bag Non-PVC, Non-DEHP, Sterile. The product should be used immediately after removal from the overwrap. If not used immediately, the storage time and conditions prior to use should not be longer than 30 days at 23°C to 27°C (73°F to 81°F). 16.2 Storage Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

16.1 How Supplied Levetiracetam in Sodium Chloride Injection is a clear, colorless, sterile solution that is available in a single-dose 100 mL dual port bag with an over wrap. The container closure is not made with natural rubber latex. It is available in the following presentations: Product Code Unit of Sale Strength Each 455000 65219-042-71 Package of 24 500 mg in 100 mL (5 mg per mL) 65219-042-21 100 mL single-dose bag 455100 65219-044-71 Package of 24 1,000 mg in 100 mL (10 mg per mL) 65219-044-21 100 mL single-dose bag 455200 65219-046-71 Package of 24 1,500 mg in 100 mL (15 mg per mL) 65219-046-21 100 mL single-dose bag Non-PVC, Non-DEHP, Sterile. The product should be used immediately after removal from the overwrap. If not used immediately, the storage time and conditions prior to use should not be longer than 30 days at 23°C to 27°C (73°F to 81°F).