Conjupri

1 INDICATIONS AND USAGE CONJUPRI ® is calcium channel blocker and may be used alone or in combination with other antihypertensive and antianginal agents for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. 1.1 Hypertension CONJUPRI ® is indicated for the treatment of hypertension in adults and patients 6 years and older, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including levamlodipine. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Levamlodipine may be used alone or in combination with other antihypertensive agents.

2 DOSAGE AND ADMINISTRATION • Adult recommended starting dose: 2.5 mg once daily with maximum dose 5 mg once daily. ( 2.1 ) ○ Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 1.25 mg once daily. ( 2.1 ) • Pediatric starting dose: 1.25 mg to 2.5 mg once daily. ( 2.2 ) Important Limitation : Doses in excess of 2.5 mg daily have not been studied in pediatric patients. ( 2.2 ) 2.1 Adults The usual initial antihypertensive oral dose of levamlodipine is 2.5 mg once daily, and the maximum dose is 5 mg once daily. Small, fragile, or elderly patients, or patients with hepatic insufficiency may be started on 1.25 mg once daily and this dose may be used when adding levamlodipine to other antihypertensive therapy. Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps. Titrate more rapidly, however, if clinically warranted, provided the patient is assessed frequently. 2.2 Children The effective antihypertensive oral dose in pediatric patients ages 6–17 years is 1.25 mg to 2.5 mg once daily. Doses in excess of 2.5 mg daily have not been studied in pediatric patients [see Clinical Pharmacology ( 12.4 ), Clinical Studies ( 14.1 )] .

3 DOSAGE FORMS AND STRENGTHS Tablet, 2.5 mg is white to off-white, capsule shaped, flat-faced tablet with functional score on each side, engraved with “OE” on one side and “B47” on the other side. Tablet of 2.5 mg can be split for 1.25 mg dose for medical conditions that need 1.25 mg dose. Tablet, 5 mg is white to off-white, soap shaped, flat-faced tablet, engraved with “OE” on one side and “B48” on the other side. Tablets: 2.5 mg (functionally scored), and 5 mg. 2.5 mg tablets can be split for 1.25 mg dose ( 3 )

4 CONTRAINDICATIONS Levamlodipine is contraindicated in patients with known sensitivity to amlodipine. Known sensitivity to amlodipine. ( 4 )

6 ADVERSE REACTIONS Most common adverse reactions to amlodipine is edema which occurred in a dose related manner. Other adverse experiences not dose related but reported with an incidence >1.0% are fatigue, nausea, abdominal pain and somnolence. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, call CSPC Ouyi Pharmaceutical Co., Ltd at 1-877-436-7220 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. Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In general, treatment with amlodipine besylate was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine besylate (N = 1730) at doses up to 10 mg to placebo (N = 1250), discontinuation of amlodipine besylate because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are reflected in the table below. The incidence (%) of side effects that occurred in a dose related manner are as follows: Amlodipine Placebo 2.5 mg 5 mg 10 mg N=275 N=296 N=268 N=520 Edema 1.8 3.0 10.8 0.6 Dizziness 1.1 3.4 3.4 1.5 Flushing 0.7 1.4 2.6 0.0 Palpitation 0.7 1.4 4.5 0.6 Other adverse reactions that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following: Amlodipine (%) Placebo (%) (N=1,730) (N=1,250) Fatigue 4.5 2.8 Nausea 2.9 1.9 Abdominal Pain 1.6 0.3 Somnolence 1.4 0.6 For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table: Amlodipine Placebo Male=% Female=% Male=% Female=% (N=1,218) (N=512) (N=914) (N=336) Edema 5.6 14.6 1.4 5.1 Flushing 1.5 4.5 0.3 0.9 Palpitations 1.4 3.3 0.9 0.9 Somnolence 1.3 1.6 0.8 0.3 The following events occurred in 0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular : arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis. Central and Peripheral Nervous System : hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo. Gastrointestinal : anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia. General : allergic reaction, asthenia,1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease. Musculoskeletal System : arthralgia, arthrosis, muscle cramps,1 myalgia. Psychiatric : sexual dysfunction (male1 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization. Respiratory System : dyspnea,1 epistaxis. Skin and Appendages : angioedema, erythema multiforme, pruritus,1 rash,1 rash erythematous, rash maculopapular. Special Senses : abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus. Urinary System : micturition frequency, micturition disorder, nocturia. Autonomic Nervous System : dry mouth, sweating increased. Metabolic and Nutritional : hyperglycemia, thirst. Hemopoietic : leukopenia, purpura, thrombocytopenia. 1 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies. Amlodipine therapy has not been associated with clinically significant changes in rou …

7 DRUG INTERACTIONS Do not exceed doses greater than 20 mg daily of simvastatin. ( 7.2 ) 7.1 Impact of Other Drugs on Amlodipine CYP3A Inhibitors Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment [see Clinical Pharmacology ( 12.3 )] CYP3A Inducers No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers. Sildenafil Monitor for hypotension when sildenafil is co-administered with amlodipine [see Clinical Pharmacology ( 12.2 )] . 7.2 Impact of Amlodipine on Other Drugs Simvastatin Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily [see Clinical Pharmacology ( 12.3 )] . Immunosuppressants Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS Pediatric: Effect on patients less than 6 years old is not known. ( 8.4 ) Geriatric: Start dosing at the low end of the dose range. ( 8.5 ) 8.1 Pregnancy Risk Summary The limited available data based on post-marketing reports with amlodipine use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy [see Clinical Considerations] . In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine during organogenesis at doses approximately 10 and 20-times the maximum recommended human dose (MRHD), respectively. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. 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. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Data Animal Data No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose. 8.2 Lactation Risk Summary Limited available data from a published clinical lactation study reports that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed. There is no available information on the effects of amlodipine on milk production. 8.4 Pediatric Use Levamlodipine (1.25 to 2.5 mg daily) is effective in lowering blood pressure in patients 6 to 17 years [see Clinical Studies ( 14.1 )] . Effect of levamlodipine on blood pressure in patients less than 6 years of age is not known. 8.5 Geriatric Use Clinical studies of amlodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40–60%, and a lower initial dose may be required [see Dosage and Administration ( 2.1 )] …

12.1 Mechanism of Action Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. Amlodipine is a 1:1 racemic mixture of levamlodipine and dextro amlodipine, it has been demonstrated that levamlodipine is the pharmacologically active, anti-hypertensive isomer.

11 DESCRIPTION The active ingredient levamlodipine maleate is the maleate salt of levamlodipine, the pharmacologically active isomer of amlodipine, a long-acting calcium channel blocker. Levamlodipine maleate is chemically described as (S)3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate maleate, and its structural formula is: Levamlodipine maleate is an off-white to light yellow crystalline powder with a molecular weight of 524.95. It is slightly soluble in water and sparingly soluble in ethanol. CONJUPRI ® (Levamlodipine) tablets are formulated as white to off-white tablets containing 1.25, 2.5, and 5 mg of levamlodipine (equivalent to 1.6, 3.2, and 6.4 mg of levamlodipine maleate respectively), for oral administration. In addition to the active ingredient, levamlodipine maleate, each tablet contains the following inactive ingredients: betadex, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. image of conjupri structure

10 OVERDOSAGE Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine limited. Single oral doses of amlodipine equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m 2 basis) caused a marked peripheral vasodilation and hypotension. If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

16 HOW SUPPLIED/STORAGE AND HANDLING 2.5 mg Tablets Levamlodipine – 2.5 mg tablets are supplied as white to off-white, capsule shaped, flat-faced tablet with functional score on each side, engraved with “OE” on one side and “B47” on the other side and supplied as follows: NDC 24075-0411-3 Bottle of 30 tablets with child-resistant closure NDC 24075-0411-9 Bottle of 90 tablets with child-resistant closure NDC 24075-0411-5 Bottle of 500 tablets 5 mg Tablets Levamlodipine – 5 mg tablets are supplied as white to off-white, soap shaped, flat-faced tablet, engraved with “OE” on one side and “B48” on the other side and supplied as follows: NDC 24075-0413-3 Bottle of 30 tablets with child-resistant closure NDC 24075-0413-9 Bottle of 90 tablets with child-resistant closure NDC 24075-0413-5 Bottle of 500 tablets Storage Store bottles at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant containers (USP). Manufactured and distributed by: CSPC Ouyi Pharmaceutical Co., Ltd. CONJUPRI ® is a registered trademark of CSPC Ouyi Pharmaceutical Co., Ltd. © 2021 CSPC Ouyi Pharmaceutical Co., Ltd.