Tri-Xenglu XR

Tablets

(Empagliflozin+Linagliptin
+Metformin HCI extended-release)

WARNING: LACTIC ACIDOSIS


ٹرائی۔ زینگلو امیکس آر ٹیلیس


⚫ Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/ml
Risk factors include renal impairment, concomitant use of certain drugs, age 265 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups should be carried out.
If lactic acidosis is suspected, discontinue Tri-Xenglu XR (Empagliflozin Linagliptin+Metformin HCI extended-release) Tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

DESCRIPTION


Tri-Xenglu XR Tablets is a prescription medicine that contains 3 diabetes medicines for oral use. which contains: Empagliflozin Linagliptin, and Metformin hydrochloride.

Empagliflozin

Empagliflozin is an inhibitor of the sodium-glucose co-transporter 2 (SGLT2). The chemical name of Empagliflozin is D-Glucitol, 1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl] oxy)phenyl] methyl]phenyl]-, (1S). The molecular formula is C23H27CIO7 and the molecular weight is 450.91. The structural formula, is:

Linagliptin

Linagliptin is an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. The chemical name of Linagliptin is 1H-Purine-2,6-dione, 8-[(3R) -3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7dihydro-3-methyl-1-[(4-meth- yl-2-quinazolinyl)methyl]. The molecular formula is C25H28N8O2 and the molecular weight is 472.54.

Metformin HCI

Metformin hydrochloride a biguanide, is an antihyperglyce mic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and. postprandial plasma glucose. The chemical name is N,N-dimethylimidodicarbonimidic diamide hydrochloride. Its molecular formula is C4HNs-HCI and a molecular weight of 165.63.

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PHARMACOLOGICAL ACTIONS

Mechanism of Action


Empagliflozin

Sodium-glucose co-transporter 2 (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation, Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, Empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

Linagliptin

Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, Linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis.

Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output.

Metformin HCI

Metformin is an anti-hyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With Metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

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Pharmacodynamics


Empagliflozin


Urinary Glucose Excretion

In patients with type 2 diabetes, urinary glucose excretion increased immediately following a dose of Empagliflozin and was maintained at the end of a 4-week treatment period averaging at approximately 64 grams per day with 10mg Empagliflozin and 78 grams per day with 25mg Empagliflozin once daily.


Cardiac Electrophysiology

No increase in QTc was observed with either 25mg or 200mg Empagliflozin. Linagliptin: Linagliptin binds to DPP-4 in a reversible manner and increases the concentrations of incretin hormones. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion, thus resulting in a better regulation of the glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposurès.


Cardiac Electrophysiology

No increase in QTc was observed with either the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose, peak Linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5-mg dose.

Pharmacokinetics

Administration of this combination with food resulted in no change in overall exposure of Empagliflozin or Linagliptin. For Metformin extended-release, high-fat meals increased systemic exposure (as measured by area-under-the-curve [AUC]) by approximately 70% relative to fasting, while Cmax is not affected. Meals prolonged Tmax by approximately 3 hours.

Empagliflozin


Absorption

The pharmacokinetics of Empagliflozin has been characterized in healthy volunteers and patients with type 2 diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of Empagliflozin were reached at 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady-state mean plasma AUC and Cmax were 1870 nmol-h/L and 259 nmol/L, respectively, with 10 mg Empagliflozin once daily treatment, and 4740 nmol-h/L and 687 nmol/L, respectively, with 25 mg Empagliflozin once daily treatment. Systemic exposure of Empagliflozin increased in a dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of Empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.


Distribution

The apparent steady-state volume of distribution was estimated to be 73.8 L based on a population pharmacokinetic analysis. Following administration of an oral [14C]-Empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36:8% and plasma protein binding was 86.2%.

Elimination

The apparent terminal elimination half-life of Empagliflozin was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with Empagliflozin half-life.

Metabolism

No major metabolites of Empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-0-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material.

Excretion

Following administration of an oral [14C]-Empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug. Linagliptin

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Linagliptin


Absorption

The absolute bioavailability of Linagliptin is approximately 30%. A high-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. Linagliptin may be administered with or without food.

Distribution

The mean apparent volume of distribution at steady-state following a single intravenous dose of Linagliptin 5 mg to healthy subjects is approximately 1110 L. indicating that Linagliptin extensively distributes to the tissues. Plasma protein binding of Linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75% to 89% at 230 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of Linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of Linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.

Elimination

Linagliptin has a terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min.

Metabolism

Following oral administration, the majority (about 90%) of Linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed Linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to Linagliptin.


Excretion

Following administration of an oral [14C]-Linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing.

Metformin HCI


Absorption

Following a single oral dose of 1000 mg (2 x 500 mg Tablets) Metformin HCI extended-release after a meal, the time to reach maximum plasma Metformin concentration (Tmax) is achieved at approximately 7 to 8 hours. In both single-and multiple-dose studies in healthy subjects, once daily 1000 mg (2 x 500 mg Tablets) dosing provides equivalent systemic exposure, as measured by AUC, and up to 35% higher Cmax of Metformin relative to the immediate-release given as 500 mg twice daily.


Single oral doses of Metformin HCI extended-release from 500 mg to 2500 mg resulted in less than proportional increase in both AUC and Cmax. Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from Metformin extended-release Tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged Metformin Tmax by approximately 3 hours but Cmax, was not affected.

Distribution

The apparent volume of distribution (V/F) of Metformin following single oral doses of immediate-release Metformin HCI Tablets 850 mg averaged 6541358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Elimination

Metformin has a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Metabolism

Intravenous single-dose studies in normal subjects demonstrate that Metformin does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Excretion

Following oral administration, approximately 90% of the absorbed drug is excreted via the renal route within the first 24 hours. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of Metformin elimination.

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Special populations


Renal Impairment

Studies characterizing the pharmacokinetics of Empagliflozin, Linagliptin, and Metformin after administration of triple combination in renally impaired patients have not been performed.

Hepatic Impairment


Triple combination

Studies characterizing the pharmacokinetics of Empagliflozin, Linagliptin, and Metformin after administration of combination in hepatically impaired patients have not been performed.

Pediatric Use

Safety and effectiveness of this combination have not been established in pediatric patients.

Geriatric Use

Assess renal function more frequently in Tri-Xenglu XR treated geriatric patients because there is a greater risk of Empagliflozin-associated intravascular volume contraction and symptomatic hypotension in geriatric patients and there is a greater risk of Metformin-associated lactic acidosis in geriatric patients.

The recommended dosage for the Metformin component of Tri-Xenglu XR in geriatric patients should usually start at the lower end of the dosage range.

INDICATIONS AND USAGE


Tri-Xenglu XR tablets is a combination of Empagliflozin, Linagliptin, and Metformin hydrochloride (HCI). It can be used:
As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
In adults with type 2 diabetes mellitus and established cardiovascular disease, when Empagliflozin is indicated to reduce the risk of cardiovascular death.


Limitations of Use

Tri-Xenglu XR is not recommended in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.
This combination has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using this combination.

DOSAGE AND ADMINISTRATION


Individualize the starting dose of Tri-Xenglu XR based on the patient’s current regimen:
In patients on Metformin HCI, with or without Linagliptin, switch to Tri-Xenglu XR containing a similar total daily dose of
Metformin HCI and a total daily dose of Empagliflozin 10mg and Linagliptin 5 mg;
In patients on Metformin HCI and any regimen containing Empagliflozin, with or without Linagliptin, switch to Tri-Xenglu XR
containing a similar total daily dose of Metformin HCI, the same total daily dose of Empagliflozin and Linagliptin 5mg.
Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dose of Empagliflozin 25mg, Linagliptin 5mg and Metformin HCI 2000 mg.
Take Tri-Xenglu XR orally, once daily with a meal in the morning.

.
Take Tri-Xenglu XR 10mg/5mg/1000 mg or Tri-Xenglu XR 25mg/5mg/1000mg as a single Tablets once daily.
Take Tri-Xenglu XR 5mg/2.5mg/1000mg or Tri-Xenglu XR 12.5mg/2.5mg/1000 mg as two Tablets together once daily. Swallow Tri-Xenglu XR Tablets whole. Do not split, crush, dissolve, or chew.

Patients with Renal Impairment

  • Initiation of Tri-Xenglu XR is not recommended in patients with an eGFR less than 45 mL/min/1.73 m2, due to the Metformin component.

    Tri-Xenglu XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 or in patients on dialysis.
  • Discontinuation for lodinated Contrast Imaging Procedures
  • Discontinue Tri-Xenglu XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart Tri-Xenglu XR if renal function is stable.

CONTRAINDICATIONS


Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end-stage renal disease, or dialysis.
Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
Hypersensitivity to Empagliflozin, Linagliptin, Metformin or any of the excipients, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred.

ADVERSE EFFECTS


The following important adverse reactions are;
.
Lactic Acidosis

  • Pancreatitis
  • Ketoacidosis
    Volume Depletion

    Urosepsis and Pyelonephritis

    .
    Genital Mycotic Infections


    Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Hypersensitivity Reactions
    .
    Vitamin B12 Deficiency Severe and Disabling Arthralgia
    .
    Bullous Pemphigoid

    Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

    Heart Failure
    WARNINGS AND DI


WARNINGS AND PRECAUTIONS


Lactic Acidosis

If Metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Tri-Xenglu XR. In Tri-Xenglu XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated Metformin (Metformin is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions).


Before initiating Tri-Xenglu XR, obtain an estimated glomerular filtration rate (eGFR). Tri-Xenglu XR is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2.


Assess renal function more frequently in elderly patients. Re-evaluate eGFR 48 hours after the imaging procedure, and restart Tri-Xenglu XR if renal function is stable.


Tri-Xenglu XR should be temporarily discontinued while patients have restricted food and fluid intake.
Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue Tri-Xenglu XR. Avoid use of Tri-Xenglu XR in patients with clinical or laboratory evidence of hepatic disease.


Pancreatitis

Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with Linagliptin: If pancreatitis is suspected, promptly discontinue Tri-Xenglu XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Tri-Xenglu XR.


Ketoacidosis

If ketoacidosis is suspected, Tri-Xenglu XR should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.


Before initiating Tri-Xenglu XR, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue Tri-Xenglu XR and seek medical attention immediately if signs and symptoms occur.


Volume Depletion

Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating Tri-Xenglu XR in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.


Urosepsis and Pyelonephritis

Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Metformin may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with Tri-Xenglu XR.

  • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Patients treated with Tri-Xenglu XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue Tri-Xenglu XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

Genital Mycotic Infections

Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat as appropriate.

Hypersensitivity Reactions

These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. If a
hypersensitivity reaction occurs, discontinue Tri-Xenglu XR, treat promptly per standard of care, and monitor until signs and
symptoms resolve.


Vitamin B12 Deficiency

Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on Tri-Xenglu XR and manage any, abnormalities.

Severe and Disabling Arthralgia

Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
Bullous Pemphigold: If bullous pemphigoid is suspected, Tri-Xenglu XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Heart Failure

Consider the risks and benefits of Tri-Xenglu XR prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of Tri-Xenglu XR.

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DRUG INTERACTIONS


Carbonic Anhydrase Inhibitors

Concomitant use of Carbonic Anhydrase Inhibitors with Tri-Xenglu XR may increase the risk of lactic acidosis. Consider more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of Metformin could increase systemic exposure to Metformin and may increase the risk for lactic
acidosis.
Diuretics: Co-administration of Empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion. Before initiating Tri-Xenglu XR, assess volume status and renal function.
Insulin or Insulin Secretagogues: Co-administration of Tri-Xenglu XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
• Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. When such drugs are administered to a patient receiving Tri-Xengiu XR, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving Tri-Xenglu XR, the patient should be observed closely for hypoglycemia.
Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring glycemic control with 1,5-AG assay is not recommended Use alternative methods to monitor glycemic control.
Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased Linagliptin exposure, suggesting that the efficacy of Linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Use of alternative treatments is strongly recommended when Linagliptin is to be administered with a strong P-gp or CYP3A4 inducer.

PREGNANCY AND LACTATION


Pregnancy

Tri-Xenglu XR is not recommended during the second and third trimesters of pregnancy.
The limited available data with Linagliptin, or Empagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage.
Lactation: There is limited information regarding the presence of combination, or its components (Empagliflozin, Linagliptin, or Metformin) in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, including the potential for Empagliflozin to affect postnatal renal development, advise patients that use of Tri-Xenglu XR is not recommended while breastfeeding.

OVERDOSE


Overdose of Metformin HCI has occurred, including ingestion of amounts greater than 50 grams. Lactic acidosis has been reported in approximately 32% of Metformin overdose cases.
Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom Metformin overdosage is suspected.
Removal of Empagliflozin by hemodialysis has not been studied, and removal of Linagliptin by hemodialysis or peritoneal dialysis is
unlikely.

INSTRUCTIONS


Store below 30°C.
Protect from sunlight and moisture.
Keep out of reach of children.

HOW SUPPLIED


Tri-Xenglu XR 5mg/2.5mg/1000mg Tablets: Alu-Alu blister pack of 2 x 7’s Tablets Tri-Xenglu XR 10mg/5mg/1000mg Tablets: Alu-Alu blister pack of 2 x 7’s Tablets Tri-Xenglu XR 12.5mg/2.5mg/1000mg Tablets: Alu-Alu blister pack of 2 x 7’s Tablets Tri-Xenglu XR 25mg/5mg/1000mg Tablets: Alu-Alu blister pack of 2 x 7’s Tablets

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