Alogliptin + Metformin
Drug Related WarningAlogliptin + Metformin
- Patients with an eGFR between 30-60 mL/minute/1.73 m², those with a history of alcoholism, liver disease, or heart failure, or those who will receive intra-arterial iodinate contrast should stop taking metformin at the time of or prior an iodinated contrast imaging treatment.
Lactic acidosis
- One rare but potentially dangerous side effect of metformin accumulation is lactic acidosis.
- They are characterized by elevated lactate/pyruvate ratio, decreased blood pH, elevated anion gap in electrolyte disorders, and blood lactate levels of more than 5 mmol/L.
- Conditions including sepsis, dehydration, excessive alcohol use, hepatic impairment, renal impairment, and acute CHF enhance risk.
- The onset is frequently gradual and is only accompanied by insufficient symptoms (such as myalgias, malaise, respiratory distress, growing somnolence, and vague abdominal distress).
- Abnormalities in the laboratory include low pH, high anion gap, and high blood lactate.
- Stop taking alogliptin and metformin and admit the patient into a hospital immediately if acidosis is detected.
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Dipeptidyl Peptidase 4 (DPP-4) Inhibitor, Biguanide, Therapy Class:
Antidiabetic Agent, Approved Countries
The United States, Canada, the United Kingdom, Germany, Australia
Alogliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptyl peptidase-4 (DPP-4) inhibitors and biguanide.
Alogliptin and metformin is a combination drug approved to treat type 2 diabetes mellitus and works by reducing blood sugar levels. When diet and exercise alone are not enough to control the blood sugar levels in people with type 2 diabetes, this combination benefits.
The side effects of Alogliptin + Metformin include diarrhoea, hypertension, headaches, back discomfort, upper respiratory tract infections, and nasopharyngitis. Hypoglycemia, or low blood sugar, is a possible side effect.
Alogliptin + Metformin is available as a tablet for convenient administration.
Alogliptin + Metformin is available in various countries worldwide, including the United States, Canada, the United Kingdom, Germany, Australia, and many others.
Alogliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptyl peptidase-4 (DPP-4) inhibitors and biguanide.
Alogliptin: Blood sugar is regulated by incretin hormones released by the small intestine, such as GLP-1 and GIP, which increase insulin secretion and decrease pancreatic glucagon. GLP-1 levels are lower in type 2 diabetes, but the insulin response remains. By blocking DPP-4 activity, the DPP-4 inhibitor alogliptin raises incretin hormone levels. In individuals with type 2 diabetes, this lowers blood sugar levels during the fasting and after meals in a glucose-dependent way.
Metformin: Metformin decreases hepatic glucose production, reduces intestinal absorption of glucose and improves the insulin sensitivity (increases peripheral glucose uptake and utilization).
The onset of action of metformin was up to 2 weeks.
Synergistic Benefits: Alogliptin + Metformin effectively treats type 2 diabetes by combining two different drugs. The DPP-4 inhibitor alogliptin improves the function of incretin hormones, which control blood sugar levels. These hormones decrease the synthesis of excess glucose and promote insulin release. Metformin is a biguanide that significantly lower hepatic glucose production and increases peripheral glucose utilization. When combined, they enhance insulin sensitivity, lower blood sugar levels after meals and during fasting, and support weight management. When lifestyle changes alone are insufficient to improve glycemic control in the individuals with type 2 diabetes, this combination therapy provides a complete approach.
Data Onset of action of Alogliptin + Metformin effects is shown typically within hours to days post-administration
Data duration of action of Alogliptin + Metformin effects may persist for several hours to days—following oral administration.
The Data of Tmax of Alogliptin + metformin generally occurs within a few hours of oral administration, leading to the onset of blood sugar-lowering effects.
The Cmax (peak plasma concentration) of Alogliptin + Metformin is typically reached within a few hours of oral administration,
Alogliptin + MetforminAlogliptin + Metformin is available in tablets.
Tablets: To be swallowed whole with water/liquid.
As the physician recommends, take the medication orally once daily, generally with or without a meal.
- Alogliptin can be used to treat Diabetes mellitus, type 2, treatment. By improving the release of insulin and reducing the quantity of glucose generated by the liver, it helps with blood sugar regulation.
- Metformin can be used to treat Diabetes mellitus, type 2, treatment. It is also used for Antipsychotic-induced weight gain; Diabetes mellitus, type 2 (prevention); Gestational diabetes mellitus (medicine); Ovarian hyperstimulation syndrome prevention in the patients with polycystic ovary syndrome undergoing in vitro fertilization/intracytoplasmic sperm injection.
- Alogliptin + Metformin is used to effectively manage blood sugar levels in individuals with type 2 diabetes, helping to improve glycemic control.
- Alogliptin + metformin therapy can help manage weight by improving the insulin sensitivity and reducing hepatic glucose production.
- This combination is an adjunct to diet and exercise when lifestyle changes alone are insufficient in controlling diabetes.
Alogliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptyl peptidase-4 (DPP-4) inhibitors and biguanide.
Alogliptin: Alogliptin helps boost the amount of insulin your body generates following a meal and prevents excessive glucose (sugar) release into the blood. In doing so, it decreases your body's blood glucose levels. It often only causes a single frequent adverse effect and is taken once each day.
Metformin: Metformin improves glucose tolerance by lowering basal and postprandial plasma glucose. It exerts its effect by decreasing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, delaying intestinal glucose absorption, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization.
Alogliptin + Metformin combination benefits diabetes by effectively improving glycemic control. It combines the effects of metformin, which lowers liver glucose production and increases insulin sensitivity, with Alogliptin, a DPP-4 inhibitor that increases incretin hormone activity. This mixture promotes weight control and lowers blood sugar, especially after meals. In situations where lifestyle modifications alone are insufficient, they provide a complete approach to glycemic management, enhancing the general health of people with type 2 diabetes.
Indicated as an additive to diet and exercise in persons with type 2 diabetes mellitus to enhance glycemic control.
This combination therapy, when indicated, can help individuals with type 2 diabetes manage their weight effectively.
Limitations on Use
Patients with type 1 diabetes mellitus should not use metformin HCl tablets or alogliptin.
Orally: Alogliptin + metformin is available as a tablet that can be taken orally. Alogliptin + metformin tablets should be taken twice daily with food to reduce the risk of gastrointestinal side effects related to metformin; splitting the pills should be avoided. Effectiveness and tolerability may dictate dosage changes, but daily maximums of 25 mg of alogliptin and 2000 mg of metformin hydrochloride (HCl) should be maintained. Healthcare providers should individualize the first dosage based on the patient's existing course of therapy.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Tablets: 12.5mg+500mg or 12.5mg+1000mg
Alogliptin + Metformin is available in the form of Oral tablets.
Dosage Adjustment for Adult Patients
Type 2 Diabetes Mellitus
Start dosage in accordance with the patient's current treatment plan.
Take PO BID with a meal and increase the dosage gradually to lessen the metformin's GI adverse effects.
No more than 25 mg or 2000 mg daily.
Alogliptin + Metformin should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.
Taking Alogliptin + metformin with food is advised for safe and effective use to lower the risk of gastrointestinal side effects. Because alcohol can interfere with blood sugar regulation, limiting consumption and talking to a healthcare professional about it is best. Long-term Metformin use may result in a vitamin B12 deficit, which should be considered. B12 supplements may be necessary. Watch out for symptoms of hypoglycemia and lactic acidosis, a rare but dangerous side effect. If surgery is scheduled, inform the surgical team about any medications you take and talk to the physician about potential drug interactions. Effective diabetes management requires following doctor's instructions about medication use, dosage adjustments, dietary advice, and routine check-ups. Advice may differ depending on individual health conditions.
It is also advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.
The dietary restriction should be individualized as per patient requirements.
Alogliptin + metformin may be contraindicated in patients with the following conditions:-
- Renal impairment (defined as eGFR <30 ml/min/1.73 m2); medical situations such as shock, severe MI, and septicemia can also cause renal impairment.
- Any metabolic acidosis, whether acute or chronic, including diabetic ketoacidosis, for which insulin should be administered
- Angioedema, anaphylaxis, and severe cutaneous adverse effects, such as Stevens-Johnson syndrome, are examples of hypersensitivity to metformin or alogliptin.
- Lactic acidosis (refer to the Black Box Cautions)
- Pancreatitis was noted.
- Reports of catastrophic and nonfatal hepatic failure, fatty liver disease, and elevated liver enzymes are additional symptoms of type 2 diabetes. If LFTs rise, closely follow the patient and stop alogliptin treatment; if another reason cannot explain liver test abnormalities, do not restart alogliptin.
- A lower insulin or insulin secretagogue dose may be required to reduce the risk of hypoglycemia because both insulin and insulin secretagogues (such as sulfonylureas) are known to cause hypoglycemia.
- When used with medications that could impact renal function or metformin excretion,
- For any surgical procedures that limit the amount of food or drink consumed, temporarily stop taking metformin.
- Hypoxic situations linked to lactic acidosis, such as shock, acute CHF, and acute MI (refer to Black Box Warnings)
- The effects of metformin on lactate metabolism are exacerbated by alcohol; limit your consumption.
- Metformin may cause levels of vitamin B12 to drop.
- Metformin may cause hypoglycemia if calorie intake is inadequate.
- Hypersensitivity reactions: Anaphylaxis, angioedema, and severe skin reactions are among the serious hypersensitivity reactions linked to the usage of alogliptin that have been recorded. Stop taking the medication, look into possible side effects, and think about getting diabetes treated differently if a significant reaction is suspected. As the risk with alogliptin is unknown, proceed cautiously in individuals who have previously experienced angioedema while taking other DPP-4 inhibitors.
- Severe and disabling arthralgia: According to postmarketing studies, some DPP-4 inhibitor users have had severe and incapacitating joint pain. These symptoms can appear for days, weeks, or years after taking the medicine. When DPP-4 inhibitors are stopped, joint pain usually goes away, but joint pain could return if one or more of them are retaken. Consequently, take DPP-4 inhibitors into account as a possible reason for excruciating joint pain and stop taking the medication if required.
- Bullous pemphigoid: Postmarketing reports have shown instances of hospitalized bullous pemphigoid that have been linked to the use of DPP-4 inhibitors. Patients usually recover after stopping the drug and receiving systemic or topical immunosuppressive therapy. When blisters or erosions appear while on treatment, patients should be instructed to report them immediately. If bullous pemphigoid is suspected, this combination should be stopped, and a dermatologist appointment is advised for a diagnosis and recommended course of treatment.
- Iodinated contrast imaging procedures: Metformin should be stopped before intra-arterial iodinated contrast imaging in patients with eGFR 30–60 mL/min/1.73 m², a history of liver disease, alcoholism, heart failure, or who are receiving it. Resume metformin and reevaluate eGFR 48 hours after the surgery if renal function is steady.
- Congestive heart failure (CHF) risk: Including 5,380 individuals with recent Acute Coronary Syndrome and type 2 diabetes, the EXAMINE experiment was conducted. It was not statistically significant that 3.9% of patients on alogliptin and 3.3% of those on placebo developed heart failure. Heart failure wasn't a research objective, but medical professionals should still check diabetes management and think about stopping alogliptin-containing drugs in people with it.
Alcohol Warning
It is unsafe to consume Alogliptin + metformin with alcohol.
Breast Feeding Warning
There is no sufficient scientific evidence traceable regarding the use and safety of Alogliptin + metformin in breastfeeding.
Pregnancy Warning
It is generally considered safe to use Alogliptin + metformin during pregnancy.
Food Warning
Minimize or avoid sugary drinks or high-carb foods like soda and fruit juices.
The adverse reactions related to Alogliptin + metformin can be categorized as
- Common Adverse Effects: Gastrointestinal symptoms like nausea, diarrhoea, abdominal discomfort and hypoglycemia.
- Less Common Adverse effects: Upper respiratory tract infection, nasopharyngitis, hypertension, headache, back pain, urinary tract infection
- Rare Adverse effects: Hypersensitivity, Pancreatitis
Reports on Postmarketing
Severe and excruciating arthralgia
Angioedema, rash, urticaria, and anaphylaxis
Serious cutaneous side effects, including Stevens-Johnson syndrome
A spike in hepatic enzymes
Liver failure with fullness
Pemphigoid bullous
The rhabdomyolysis
Constipation
Nausea
Renal and urinary disorders: Tubulointerstitial nephritis
Illus
Adverse Effects
The clinically relevant drug interactions of Alogliptin + Metformin are briefly summarized here.
- Medications Affecting Blood Glucose: Medications like insulin, sulfonylureas, or other anti-diabetic agents may require dose adjustments when taken with Alogliptin + metformin to avoid hypoglycemia.
- Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) may interact with metformin, potentially increasing its levels and the risk of lactic acidosis.
- Diuretics: Diuretics, such as thiazides or loop diuretics, can potentiate the effects of metformin by leading to dehydration or affecting renal function.
- Medications Affecting Blood Glucose: Medications like insulin, sulfonylureas, or other anti-diabetic agents may require dose adjustments when taken with Alogliptin + metformin to avoid hypoglycemia.
- Carbonic Anhydrase Inhibitors (e.g., Topiramate): Concurrent use can lead to high blood acidity (metabolic acidosis).
- Rifampin: Rifampin may reduce the therapeutic effects of metformin. Dose adjustments may be necessary.
- Other Medications: Concurrent use with certain medications, including cimetidine, furosemide, nifedipine, ranolazine, and vandetanib, might necessitate dose adjustments due to potential interactions.
The most common side effects of Alogliptin + metformin include-
Infection of the upper respiratory tract
Nasopharyngitis is an inflammation of the nasal passages and throat.
Vomiting
Raised blood pressure
Headache
Pain in the back
Urinary tract infection
Diarrhea
Bloating
Weakness
Indigestion
Discomfort in the abdomen
Loss of appetite
Reduced clearance of creatinine
Elevated lipase levels in the blood
- Pregnancy
Pregnancy Category B (FDA): Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.
A pregnancy with poorly controlled diabetes poses threats for both the mother and the fetus. There is no conclusive evidence linking the use of metformin during pregnancy to a significant increased risk of miscarriage or congenital impairment in published research. The limited data on pregnant women does not inform a drug-associated risk for significant congenital disabilities and miscarriage.
Preterm delivery, stillbirth, spontaneous abortions, diabetic ketoacidosis, pre-eclampsia, and delivery problems are among the risks that pregnant women with poorly controlled diabetes face. Uncontrolled diabetes raises the risk of severe congenital disabilities, macrosomia-related morbidity, and stillbirth in fetuses.
- Nursing Mothers
No evidence is available about the presence of metformin or alogliptin in human milk, how they affect breastfed infants, or how they affect milk production. Metformin is found in human milk, according to a few published studies; however, there is not enough information to determine how metformin affects breastfed infants or milk production. The benefits of breastfeeding for development and health should be considered, along with the mother's clinical need for therapy and any potential adverse effects on the breastfed child from treatment or an underlying maternal condition.
- Pediatric Use
As per FDA, safety and effectiveness in the pediatric population have not been established.
- Geriatric Use
There is currently insufficient data on the safety and efficacy of Alogliptin + metformin in elderly patients. Due to age-related physiological changes, elderly people may be more vulnerable to potential adverse effects and need regular monitoring. Determining the best course of action for each patient requires a thorough assessment of their medical background and risk factors.
Dose Adjustment in Kidney Impairment Patients:
Before beginning metformin, ascertain eGFR.
eGFR <30 mL/min/1.73 m²: Not recommended.
1.73 m²/min or 30-45 mL/min: Not advised to start a treatment.
Check eGFR at least once a year or more frequently if you are at risk of renal impairment (older people).
When taking metformin, if eGFR drops below 45 mL/min/1.73 m², the risks and benefits of continuing medication should be assessed.
Stop taking metformin if the eGFR falls to less than 30 mL/min/1.73 m².
Dose Adjustment in Hepatic Impairment Patients:
In some instances, lactic acidosis has been associated with the use of metformin in patients with hepatic impairment. Metformin HCl and alogliptin tablets should not be used when a patient has liver impairment.
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Alogliptin + Metformin.
Overconsumption of Alogliptin + metformin could lead to hypoglycemia (sweating, confusion, tremors), gastrointestinal symptoms (nausea, vomiting), and potential lactic acidosis (muscle pain, weakness, rapid breathing).
Management
There is no specific antidote or treatment for excessive intake of Alogliptin + Metformin. However, immediate medical attention is essential. Alogliptin + Metformin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.
To raise blood sugar levels, oral carbohydrates should be given to treat mild hypoglycemia (low blood sugar). Intravenous dextrose may be necessary for more severe hypoglycemia. It is crucial to continuously check kidney function, electrolytes, and blood sugar. Bicarbonate treatment and supportive care may be required when lactic acidosis is suspected. It is essential to get medical help as soon as possible if they have overdosed so that it can be appropriately evaluated and managed.
Pharmacodynamic
Alogliptin: After a single dosage is administered to healthy participants, DPP-4 inhibition peaks 2-3 hours later. Between dosages of 12.5 mg and 800 mg, DPP-4's peak inhibition approached 93%. For dosages more than or equivalent to 25 mg, the DPP-4 inhibition remained over 80% after 24 hours. Compared to placebo over 8 hours following a typical meal, an alogliptin equivalently showed reductions in postprandial glucagon while boosting postprandial active GLP-1 levels. The QTc interval is not impacted by alogliptin.
Metformin: Metformin is an antihyperglycemic medication that lowers basal and postprandial plasma glucose levels in people with type 2 diabetes, improving their glucose tolerance. Its pharmacologic modes of action are distinct from those of other oral antihyperglycemic medication groups. Metformin increases peripheral glucose uptake and utilization, which lowers intestinal glucose absorption, lowers hepatic glucose synthesis, and enhances insulin sensitivity. Metformin, in contrast to sulfonylureas, does not result in hyperinsulinemia or hypoglycemia in either type 2 diabetes patients or healthy persons. Metformin medication does not alter insulin secretion, although it may reduce the plasma insulin response throughout the day and insulin levels while fasting.
Pharmacokinetics
Absorption
Alogliptin: Tablets of alogliptin have about 100% absolute bioavailability. The total and peak exposure to alogliptin are unaffected when the medication is administered together with a high-fat meal. As a result, either a meal or no food may be consumed with alogliptin pills.
Bioavailability: ~100%
Peak plasma time: 1-2 hr (alogliptin)
Metformin: Slowly and incompletely absorbed from the gastrointestinal tract. Food slightly delays and decreases the extent of absorption. Absolute bioavailability: 50-60%. Time to peak plasma concentration: 2-3 hours (immediate-release); 7 hours, range: 4-8 hours (extended-release).
Bioavailability: 50-60% (metformin [fasted])
Distribution
Alogliptin: The volume of distribution at the terminal phase was 417 L after a single 12.5 mg intravenous infusion of alogliptin in healthy people, indicating that the drug is well dispersed into tissues.
Vd: 417 L (alogliptin)
Protein-bound: 20%
Metformin: Concentrates in the liver, kidney and gastrointestinal tract. It crosses the placenta and then enters breast milk (small amounts). Volume of distribution: 654 ± 358 L.
Protein-bound: Negligible (metformin)
Metabolism
Alogliptin: Alogliptin doesn't go through an extensive amount of metabolism. N-demethylated alogliptin (1% of parent molecule) and N-acetylated alogliptin (6% of parent compound) were two minor metabolites. The N-demethylated metabolite inhibits DPP-4 and is active. The N-acetylated metabolite has no functional effect. Cytochrome enzymes CYP2D6 and CYP3A4 are involved in the metabolism of alogliptin. However, this is only partially the case. The cytochrome enzymes in the liver metabolize 10–20% of the dosage.
Active metabolite: N-demethylated (<1% of parent compound)
Inactive metabolite: N-acetylated alogliptin (<6% of parent compound)
Minor substrate of CYP3A4 and CYP2D6
Metformin: Excreted unchanged in the urine and did not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.
Elimination
Alogliptin: The primary route of [14C] alogliptin-derived radioactivity elimination is renal excretion (76%), with 13% recovered in the faeces, resulting in a total recovery of 89% of the injected radioactive dosage. The systemic clearance of alogliptin was 14.0 L/hr, while the renal clearance of 9.6 L/hr indicated some active renal tubular secretion.
Half-life: 21 hr
Renal clearance: 9.6 L/hr
Total body clearance: 14 L/hr
Excretion: 76% urine; 13% feces
Metformin: With a plasma elimination half-life of roughly 6.2 hours, 90% of the absorbed medication is excreted via the renal pathway during the first 24 hours following oral administration. The elimination half-life of blood is roughly 17.6 hours, indicating that the erythrocyte bulk could constitute a distribution compartment.
Therapeutic benefits of Alogliptin + Metformin combination
- Metformin and alogliptin, a DPP-4 inhibitor, combine to reduce blood sugar levels. Glucose-dependent insulin production is stimulated by incretin hormones like GLP-1, which are elevated when alogliptin is taken. Metformin improves peripheral tissue insulin sensitivity by mainly addressing the synthesis of glucose in the liver. By efficiently lowering blood sugar levels during fasting and after meals, this dual mechanism aids patients in improving their glycemic control.
- The combination is a safer option for people at risk of hypoglycemia episodes because it reduces the risk of hypoglycemia as compared to sulfonylureas. By doing this, the risk of hypoglycemia-related problems is decreased.
- Alogliptin and metformin are usually weight-neutral or cause minimal weight gain when taken together. This advantage contrasts with several other anti-diabetic drugs that can cause weight gain. In addition to helping patients, it also helps to maintain a healthier body weight, the combo promotes long-term adherence to treatment strategies.
- Kaku K, Sumino S, et al. Randomized, double-blind, phase III study to evaluate the the efficacy and safety of once-daily treatment with alogliptin and metformin hydrochloride in the Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2017 Mar;19(3):463-467. doi: 10.1111/dom.12837. Epub 2017 Jan 19. PMID: 27891757; PMCID: PMC5599944.
- White WB, Heller SR, Cannon CP, Howitt H, Khunti K, Bergenstal RM; EXAMINE Investigators. Alogliptin in the Patients with Type 2 Diabetes Receiving Metformin and Sulfonylurea Therapies in the EXAMINE Trial. Am J Med. 2018 Jul;131(7):813-819.e5. doi: 10.1016/j.amjmed.2018.02.023. Epub 2018 Mar 23. PMID: 29581078.
- Takeshita Y, Kita Y, Kato KI, Kanamori T, Misu H, Kaneko S, Takamura T. Effects of metformin and alogliptin on body composition in people with type 2 diabetes. J Diabetes Investig. 2019 May;10(3):723-730. doi: 10.1111/jdi.12920. Epub 2018 Oct 25. PMID: 30156056; PMCID: PMC6497598.
- Yamazaki S, Takano T, Tachibana K, Takeda S, Terauchi Y. Comparison of the Effectiveness of Once-Daily Alogliptin/Metformin and Twice-Daily Anagliptin/Metformin Combination Tablet in a Randomized, Parallel-Group, Open-Label Trial in Japanese Patients with Type 2 Diabetes. Diabetes Ther. 2022 Aug;13(8):1559-1569. doi: 10.1007/s13300-022-01292-2. Epub 2022 Jul 6. PMID: 35793047; PMCID: PMC9309109.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14d98490-4f8f-4d2f-a4e9-7a3d7a0199ba
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203414s008s009lbl.pdf
https://www.medicines.org.uk/emc/product/5234/smpc
https://www.ncbi.nlm.nih.gov/books/NBK349228/
Published on: 23 Oct 2023 10:12 AM GMT