Alendronat Sandoz may be available in the countries listed below.
Alendronic Acid sodium trihydrate (a derivative of Alendronic Acid) is reported as an ingredient of Alendronat Sandoz in the following countries:
International Drug Name Search
Ranitidin Siga may be available in the countries listed below.
Ranitidine hydrochloride (a derivative of Ranitidine) is reported as an ingredient of Ranitidin Siga in the following countries:
International Drug Name Search
Elcal Forte may be available in the countries listed below.
Calcium Carbonate is reported as an ingredient of Elcal Forte in the following countries:
International Drug Name Search
Cortisonacetaat may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Cortisone 21-acetate (a derivative of Cortisone) is reported as an ingredient of Cortisonacetaat in the following countries:
International Drug Name Search
Damicol may be available in the countries listed below.
Fluconazole is reported as an ingredient of Damicol in the following countries:
International Drug Name Search
Ceva Albendazole may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Albendazole is reported as an ingredient of Ceva Albendazole in the following countries:
Selenium is reported as an ingredient of Ceva Albendazole in the following countries:
International Drug Name Search
Propecia is a brand name of finasteride, approved by the FDA in the following formulation(s):
A generic version of Propecia has been approved by the FDA. However, this does not mean that the product will necessarily be commercially available - possibly because of drug patents and/or drug exclusivity. The following products are equivalent to Propecia and have been approved by the FDA:
Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Propecia. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.
See also: About generic drugs.
Patents are granted by the U.S. Patent and Trademark Office at any time during a drug's development and may include a wide range of claims.
Cofamycine may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Colistin sulfate (a derivative of Colistin) is reported as an ingredient of Cofamycine in the following countries:
Spiramycin adipate (a derivative of Spiramycin) is reported as an ingredient of Cofamycine in the following countries:
International Drug Name Search
Alendronato Germed may be available in the countries listed below.
Alendronic Acid sodium trihydrate (a derivative of Alendronic Acid) is reported as an ingredient of Alendronato Germed in the following countries:
International Drug Name Search
Claudicat may be available in the countries listed below.
Pentoxifylline is reported as an ingredient of Claudicat in the following countries:
International Drug Name Search
Momendol may be available in the countries listed below.
Naproxen is reported as an ingredient of Momendol in the following countries:
Naproxen sodium salt (a derivative of Naproxen) is reported as an ingredient of Momendol in the following countries:
International Drug Name Search
Erysol may be available in the countries listed below.
Erythromycin is reported as an ingredient of Erysol in the following countries:
International Drug Name Search
Kirim may be available in the countries listed below.
Bromocriptine mesilate (a derivative of Bromocriptine) is reported as an ingredient of Kirim in the following countries:
International Drug Name Search
Microgynon may be available in the countries listed below.
Ethinylestradiol is reported as an ingredient of Microgynon in the following countries:
Levonorgestrel is reported as an ingredient of Microgynon in the following countries:
International Drug Name Search
Colina cloruro may be available in the countries listed below.
Colina cloruro (DCIT) is known as Choline in the US.
International Drug Name Search
Glossary
| DCIT | Denominazione Comune Italiana |
Hansepran may be available in the countries listed below.
Clofazimine is reported as an ingredient of Hansepran in the following countries:
International Drug Name Search
Atropina Solfato may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Atropine sulfate (a derivative of Atropine) is reported as an ingredient of Atropina Solfato in the following countries:
International Drug Name Search
Busipron-Egis may be available in the countries listed below.
Buspirone hydrochloride (a derivative of Buspirone) is reported as an ingredient of Busipron-Egis in the following countries:
International Drug Name Search
Pantodac may be available in the countries listed below.
Pantoprazole is reported as an ingredient of Pantodac in the following countries:
Pantoprazole sodium (a derivative of Pantoprazole) is reported as an ingredient of Pantodac in the following countries:
International Drug Name Search
Neo-Eunomin may be available in the countries listed below.
Chlormadinone 17α-acetate (a derivative of Chlormadinone) is reported as an ingredient of Neo-Eunomin in the following countries:
Ethinylestradiol is reported as an ingredient of Neo-Eunomin in the following countries:
International Drug Name Search
Gentamycin Actavis Ointment may be available in the countries listed below.
Gentamicin is reported as an ingredient of Gentamycin Actavis Ointment in the following countries:
International Drug Name Search
Biracin may be available in the countries listed below.
Tobramycin is reported as an ingredient of Biracin in the following countries:
International Drug Name Search
Paracetamol Mundogen may be available in the countries listed below.
Paracetamol is reported as an ingredient of Paracetamol Mundogen in the following countries:
International Drug Name Search
Estracombi may be available in the countries listed below.
Estradiol is reported as an ingredient of Estracombi in the following countries:
Norethisterone 17ß-acetate (a derivative of Norethisterone) is reported as an ingredient of Estracombi in the following countries:
International Drug Name Search
Caropram may be available in the countries listed below.
Doxapram hydrochloride (a derivative of Doxapram) is reported as an ingredient of Caropram in the following countries:
International Drug Name Search
Diltiazem Hydrochloride (BANM, JAN, USAN) is known as Diltiazem in the US.
International Drug Name Search
Glossary
| BANM | British Approved Name (Modified) |
| JAN | Japanese Accepted Name |
| USAN | United States Adopted Name |
Amantadina Level may be available in the countries listed below.
Amantadine hydrochloride (a derivative of Amantadine) is reported as an ingredient of Amantadina Level in the following countries:
International Drug Name Search
Spacin may be available in the countries listed below.
Sparfloxacin is reported as an ingredient of Spacin in the following countries:
International Drug Name Search
Ventor may be available in the countries listed below.
Nimesulide is reported as an ingredient of Ventor in the following countries:
International Drug Name Search
Chloramine T may be available in the countries listed below.
In some countries, this medicine may only be approved for veterinary use.
Tosylchloramide Sodium is reported as an ingredient of Chloramine T in the following countries:
International Drug Name Search
Airomate may be available in the countries listed below.
Afloqualone is reported as an ingredient of Airomate in the following countries:
International Drug Name Search
Adrenoxyl may be available in the countries listed below.
Carbazochrome is reported as an ingredient of Adrenoxyl in the following countries:
International Drug Name Search
Doxy Disp may be available in the countries listed below.
Doxycycline monohydrate (a derivative of Doxycycline) is reported as an ingredient of Doxy Disp in the following countries:
International Drug Name Search
Chloortalidon PCH may be available in the countries listed below.
Chlortalidone is reported as an ingredient of Chloortalidon PCH in the following countries:
International Drug Name Search
Rec.INN
B06AA04,S01KX01
0009004-07-3
Anti-inflammatory agent
Proteolytic enzyme
Chymotrypsin
International Drug Name Search
Glossary
| BAN | British Approved Name |
| DCF | Dénomination Commune Française |
| DCIT | Denominazione Comune Italiana |
| OS | Official Synonym |
| PH | Pharmacopoeia Name |
| Rec.INN | Recommended International Nonproprietary Name (World Health Organization) |
Colfem may be available in the countries listed below.
Naproxen sodium salt (a derivative of Naproxen) is reported as an ingredient of Colfem in the following countries:
International Drug Name Search
Dulcolan may be available in the countries listed below.
Bisacodyl is reported as an ingredient of Dulcolan in the following countries:
International Drug Name Search
Cordiami Guttae may be available in the countries listed below.
Nikethamide is reported as an ingredient of Cordiami Guttae in the following countries:
International Drug Name Search
Tigason may be available in the countries listed below.
Etretinate is reported as an ingredient of Tigason in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
Chorionic Gonadotrophin is reported as an ingredient of Chlorulon in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
Tylosin phosphate (a derivative of Tylosin) is reported as an ingredient of Gilt Edge Tylan in the following countries:
International Drug Name Search
Aspirina Biocrom may be available in the countries listed below.
Acetylsalicylic Acid is reported as an ingredient of Aspirina Biocrom in the following countries:
International Drug Name Search
Efadermin may be available in the countries listed below.
Lithium succinate (a derivative of Lithium) is reported as an ingredient of Efadermin in the following countries:
Zinc Sulfate is reported as an ingredient of Efadermin in the following countries:
International Drug Name Search
Yalone may be available in the countries listed below.
Methylprednisolone is reported as an ingredient of Yalone in the following countries:
International Drug Name Search
Claritromicina Juventus may be available in the countries listed below.
Clarithromycin is reported as an ingredient of Claritromicina Juventus in the following countries:
International Drug Name Search
HIV quickly develops resistance when delavirdine is used alone. Therefore, delavirdine must always be used with other proven combinations of anti-HIV medicines.
Treating HIV-1 infection. It must be used in combination with at least 2 other anti-HIV medicines.
Delavirdine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). It works by inhibiting the growth of HIV, the virus that causes AIDS.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Delavirdine. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Delavirdine. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Delavirdine may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Delavirdine as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Delavirdine.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Bronchitis; depression; diarrhea; headache; nausea; redistribution of body fat; sleeplessness; stomach pain.
Severe allergic reactions (rash; hives; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blisters; eye infection; fever; inflammation of the eye; mouth sores; muscle or joint pain; rash; swelling.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Delavirdine side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Store Delavirdine at room temperature, between 68 and 77 degrees F (20 and 25 degrees C), in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Delavirdine out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Delavirdine. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Generic Name: methadone (METH a done)
Brand Names: Diskets, Dolophine, Methadose
Methadone is a narcotic pain reliever, similar to morphine. Methadone also reduces withdrawal symptoms in people addicted to heroin or other narcotic drugs without causing the "high" associated with the drug addiction.
Methadone is used as a pain reliever and as part of drug addiction detoxification and maintenance programs.
Methadone may also be used for purposes not listed in this medication guide.
Like other narcotic medicines, methadone can slow your breathing, even long after the pain-relieving effects of the medication wear off. Death may occur if breathing becomes too weak. Never use more methadone than your doctor has prescribed. Call your doctor if you think the medicine is not working.
To make sure you can safely use methadone, tell your doctor if you have any of these other conditions:
a personal or family history of "Long QT syndrome";
asthma, COPD, sleep apnea, or other breathing disorders;
underactive thyroid;
curvature of the spine;
a history of head injury or brain tumor;
epilepsy or other seizure disorder;
low blood pressure;
gallbladder disease;
Addison's disease or other adrenal gland disorders;
enlarged prostate, urination problems;
mental illness; or
a history of drug or alcohol addiction.
Older adults and people with debilitating conditions may be more sensitive to the effects of this medication.
Use exactly as prescribed. Never use Methadone in larger amounts, or for longer than recommended by your doctor. Follow the directions on your prescription label. Tell your doctor if the medicine seems to stop working as well in relieving your pain.
Like other narcotic medicines, methadone can slow your breathing, even long after the pain-relieving effects of the medication wear off. Death may occur if breathing becomes too weak. Never use more methadone than your doctor has prescribed. Call your doctor if you think the medicine is not working.
When methadone is used as part of a treatment program for drug addiction or detoxification, you will receive the medication through a clinic or special pharmacy.
Your doctor may recommend that methadone be given to you by a family member or other caregiver. This is to make sure you are using the medicine as it was prescribed as part of your treatment.
Additional forms of counseling and/or monitoring may be recommended during treatment with methadone.
Methadone is available in tablets, dispersible tablets, oral solution (liquid) and as an injection. The pill and oral liquid forms of methadone must never be used to make a methadone injection.
Measure the liquid form of methadone with a special dose-measuring spoon or cup, not a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
The methadone dispersible tablet (Diskets) is made to be dissolved in water. Do not chew, crush, or swallow the tablet whole. Place the tablet into a 4-ounce glass of water, orange juice, or other citrus-flavored non-alcoholic beverage and allow the tablet to disperse in the liquid. The tablet will not dissolve completely. Drink this mixture right away. To make sure you get the entire dose, add a little more liquid to the same glass, swirl gently and drink right away.
After you have stopped using this medication, flush any unused pills down the toilet.
Keep track of how much of this medicine has been used. Methadone is a drug of abuse and you should be aware if any person in the household is using this medicine improperly or without a prescription.
Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.
Overdose symptoms may include extreme drowsiness, pinpoint pupils, confusion, cold and clammy skin, weak pulse, shallow breathing, fainting, or breathing that stops.
shallow breathing;
hallucinations or confusion;
chest pain, dizziness, fainting, fast or pounding heartbeat; or
trouble breathing, feeling light-headed, or fainting.
Less serious side effects may include:
feeling anxious, nervous, or restless;
sleep problems (insomnia);
feeling weak or drowsy;
dry mouth, nausea, vomiting, diarrhea, constipation, loss of appetite; or
decreased sex drive, impotence, or difficulty having an orgasm.
This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.
a diuretic (water pill);
antibiotics such as azithromycin (Zithromax), ciprofloxacin (Cipro), clarithromycin (Biaxin), erythromycin (E-Mycin, Ery-Tab), itraconazole (Sporanox), ketoconazole (Nizoral), metronidazole (Flagyl) or voriconazole (Vfend);
heart or blood pressure medication such as diltiazem (Cardizem, Dilacor, Tiazac) or verapamil (Calan, Covera, Isoptin, Verelan);
HIV medicines such as abacavir (Ziagen), amprenavir (Agenerase), didanosine (Videx), efavirenz (Sustiva), lopinavir/ritonavir (Kaletra), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir), stavudine (Zerit), or zidovudine (Retrovir);
an MAO inhibitor such as isocarboxazid (Marplan), tranylcypromine (Parnate), phenelzine (Nardil), or selegiline (Eldepryl, Emsam);
other narcotic medications such as pentazocine (Talwin), nalbuphine (Nubain), buprenorphine (Subutex), or butorphanol (Stadol);
rifampin (Rifadin, Rimactane, Rifater); or
seizure medication such as phenobarbital (Luminal, Solfoton) or phenytoin (Dilantin).
This list is not complete and there are many other drugs that can interact with Methadone. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.
See also: Dolophine side effects (in more detail)
Lisinopril Hexal may be available in the countries listed below.
Lisinopril dihydrate (a derivative of Lisinopril) is reported as an ingredient of Lisinopril Hexal in the following countries:
International Drug Name Search
Cloreto de potássio may be available in the countries listed below.
Potassium Chloride is reported as an ingredient of Cloreto de potássio in the following countries:
International Drug Name Search
Lamotrigina Merck may be available in the countries listed below.
Lamotrigine is reported as an ingredient of Lamotrigina Merck in the following countries:
International Drug Name Search
Naproxene Germed may be available in the countries listed below.
Naproxen is reported as an ingredient of Naproxene Germed in the following countries:
International Drug Name Search
ACB may be available in the countries listed below.
Acebutolol is reported as an ingredient of ACB in the following countries:
Acebutolol hydrochloride (a derivative of Acebutolol) is reported as an ingredient of ACB in the following countries:
International Drug Name Search
Claritromicina Pharmakern may be available in the countries listed below.
Clarithromycin is reported as an ingredient of Claritromicina Pharmakern in the following countries:
International Drug Name Search
Betamethason Hexal comp. may be available in the countries listed below.
Betamethasone 17α,21-dipropionate (a derivative of Betamethasone) is reported as an ingredient of Betamethason Hexal comp. in the following countries:
Salicylic Acid is reported as an ingredient of Betamethason Hexal comp. in the following countries:
International Drug Name Search
Lactulose-saar may be available in the countries listed below.
Lactulose is reported as an ingredient of Lactulose-saar in the following countries:
International Drug Name Search
Kétoprofène Ranbaxy may be available in the countries listed below.
Ketoprofen is reported as an ingredient of Kétoprofène Ranbaxy in the following countries:
International Drug Name Search
Aspen Ondansetron may be available in the countries listed below.
Ondansetron hydrochloride dihydrate (a derivative of Ondansetron) is reported as an ingredient of Aspen Ondansetron in the following countries:
International Drug Name Search
Elleste Duet may be available in the countries listed below.
UK matches:
Estradiol hemihydrate (a derivative of Estradiol) is reported as an ingredient of Elleste Duet in the following countries:
Norethisterone 17ß-acetate (a derivative of Norethisterone) is reported as an ingredient of Elleste Duet in the following countries:
International Drug Name Search
Glossary
| SPC | Summary of Product Characteristics (UK) |
Clathrocyn may be available in the countries listed below.
Clarithromycin is reported as an ingredient of Clathrocyn in the following countries:
International Drug Name Search
EpiPen Junior may be available in the countries listed below.
Epinephrine is reported as an ingredient of EpiPen Junior in the following countries:
International Drug Name Search
Aspirisucre may be available in the countries listed below.
Acetylsalicylic Acid is reported as an ingredient of Aspirisucre in the following countries:
International Drug Name Search
Zestozide may be available in the countries listed below.
Hydrochlorothiazide is reported as an ingredient of Zestozide in the following countries:
Lisinopril is reported as an ingredient of Zestozide in the following countries:
International Drug Name Search
Fusiderm may be available in the countries listed below.
Fusidic Acid is reported as an ingredient of Fusiderm in the following countries:
Fusidic Acid sodium (a derivative of Fusidic Acid) is reported as an ingredient of Fusiderm in the following countries:
International Drug Name Search
Komezol may be available in the countries listed below.
Omeprazole is reported as an ingredient of Komezol in the following countries:
International Drug Name Search
Quinace Co may be available in the countries listed below.
Hydrochlorothiazide is reported as an ingredient of Quinace Co in the following countries:
Quinapril is reported as an ingredient of Quinace Co in the following countries:
International Drug Name Search
Fabofurox may be available in the countries listed below.
Furosemide is reported as an ingredient of Fabofurox in the following countries:
International Drug Name Search
In some countries, this medicine may only be approved for veterinary use.
Sulfadimidine is reported as an ingredient of Havaspan in the following countries:
International Drug Name Search
Enalapril plus-1A Pharma may be available in the countries listed below.
Enalapril maleate (a derivative of Enalapril) is reported as an ingredient of Enalapril plus-1A Pharma in the following countries:
Hydrochlorothiazide is reported as an ingredient of Enalapril plus-1A Pharma in the following countries:
International Drug Name Search
Eff-Pha Vitamin C may be available in the countries listed below.
Ascorbic Acid is reported as an ingredient of Eff-Pha Vitamin C in the following countries:
International Drug Name Search
Salbumol Chrono may be available in the countries listed below.
Salbutamol sulfate (a derivative of Salbutamol) is reported as an ingredient of Salbumol Chrono in the following countries:
International Drug Name Search
Tobrom may be available in the countries listed below.
Tobramycin is reported as an ingredient of Tobrom in the following countries:
International Drug Name Search
Mictonetten may be available in the countries listed below.
Propiverine hydrochloride (a derivative of Propiverine) is reported as an ingredient of Mictonetten in the following countries:
International Drug Name Search
Riomet (metformin hydrochloride oral solution) is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride, USP (N,N- dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:
Metformin hydrochloride, USP is a white crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride, USP 2.0 g is soluble in 20 mL of water. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
Riomet contains 500 mg of metformin hydrochloride, USP per 5 mL and the following inactive ingredients: Cherry flavor, hydrochloric acid, potassium bicarbonate, purified water, saccharin calcium, and xylitol.
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Two pharmacokinetic studies have been performed in healthy volunteers to evaluate the bioavailability of Riomet in comparison with the commercially available metformin tablets under fasting and fed conditions (study 1 and study 2). A third pharmacokinetic study (study 3) assessed effects of food on absorption of Riomet.
The rate and extent of absorption of Riomet was found to be comparable to that of Metformin tablets under fasting or fed conditions (see Table 1).
The food-effect study (study 3) assessed the effects of a high fat/high calorie meal and a low fat/low calorie meal on the bioavailability of Riomet in comparison with administration in the fasted state, in healthy volunteers. The extent of absorption was increased by 21% and 17% with the low fat/low calorie meal and the high fat/high calorie meal, respectively, compared with the administration in the fasted state. The rate and extent of absorption with high fat/high calorie and low fat/low calorie meal were similar. The mean t max was 2.5 hours under fasting conditions as compared to 3.9 hours with both low fat/ low calorie meal and high fat/high calorie meals (see Table 2).
| Meal type | Cmax(ng/mL) | AUC0-∞ (ng.h/mL) | tmax (h) |
| Fasting (F) | 1641.5 ± 551.8 | 9982.9 ± 2544.5 | 2.5 ± 0.9 |
| Low fat/ low calorie meal (L) | 1525.8 ± 396.7 | 11542.0 ± 2947.5 | 3.9 ± 0.6 |
| High fat/high calorie meal (H) | 1432.5 ± 346.8 | 11184.5 ± 2446.1 | 3.9 ± 0.8 |
| L/F Ratio X 100 (90% confidence interval) | 94.6 (84.0-106.5) | 115.6 (103.6-128.9) | - |
| H/F Ratio X 100 (90% confidence interval) | 89.4 (79.4-100.6) | 112.6 (100.9-125.6) | - |
| L/H Ratio X 100 (90% confidence interval) | 105.8 (94.0-119.2) | 102.7 (92.0-114.6) | - |
Studies using single oral doses of metformin tablet formulations 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 µg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mg/mL, even at maximum doses.
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 3) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with 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.
In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 3), nor is there any accumulation of metformin in either group at usual clinical doses.
In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 3; also see WARNINGS).
No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 3). Riomet (metformin hydrochloride oral solution) treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. (See WARNINGS and DOSAGE AND ADMINISTRATION).
After administration of a single oral metformin 500 mg dose with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51), and Hispanics (n= 24).
In a double-blind, placebo-controlled, multicenter U.S. clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with metformin (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 4).
A 29-week, double-blind, placebo-controlled study of metformin and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 5). Patients randomized to the combination arm started therapy with metformin 500 mg and glyburide 20 mg. At the end of each week of the first four weeks of the trial, these patients had their dosages of metformin increased by 500 mg if they had failed to reach target fasting plasma glucose. After week four, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin 2500 mg. Patients in the metformin only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking metformin 2000 mg/glyburide 20 mg or metformin 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to metformin (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of metformin and glyburide was effective in reducing FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were -77 mg/dL, -68 mg/dL, and -1.9%, respectively (see Table 5).
The magnitude of the decline in fasting blood glucose concentration following the institution of metformin therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin.
In clinical studies, metformin, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels and had no adverse effects on other lipid levels (see Table 6).
| Metformin vs Placebo | Combined Metformin/Glyburide vs Monotherapy | ||||
| Metformin (n = 141) | Placebo (n = 145) | Metformin (n = 210) | Metformin/Glyburide (n = 213) | Glyburide (n = 209) | |
| Total Cholesterol (mg/dL) | |||||
| Baseline | 211.0 | 212.3 | 213.1 | 215.6 | 219.6 |
| Mean % Change at FINAL VISIT | -5% | 1% | -2% | -4% | 1% |
| Total Triglycerides (mg/dL) | |||||
| Baseline | 236.1 | 203.5 | 242.5 | 215.0 | 266.1 |
| Mean % Change at FINAL VISIT | -16% | 1% | -3% | -8% | 4% |
| LDL-Cholesterol (mg/dL) | |||||
| Baseline | 135.4 | 138.5 | 134.3 | 136.0 | 137.5 |
| Mean % Change at FINAL VISIT | -8% | 1% | -4% | -6% | 3% |
| HDL-Cholesterol (mg/dL) | |||||
| Baseline | 39.0 | 40.5 | 37.2 | 39.0 | 37.0 |
| Mean % Change at FINAL VISIT | 2% | -1% | 5% | 3% | 1% |
In contrast to sulfonylureas, body weight of individuals on metformin tended to remain stable or even decrease somewhat (see Tables 4 and 5).
A 24-week, double-blind, placebo-controlled study of metformin plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 7). Patients randomized to receive metformin plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs. 110.6 U/day, metformin plus insulin versus insulin plus placebo, respectively, p = 0.04.
A second double-blind, placebo-controlled study (n = 51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA1c of 7.46 ± 0.97%, the addition of metformin maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of metformin plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p = 0.01.
In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with metformin (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 8).
Riomet (metformin hydrochloride oral solution) is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.
Riomet is contraindicated in patients with:
1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS).
2. Known hypersensitivity to metformin hydrochloride.
3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
Riomet should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS).
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Riomet; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (> 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels > 5 µg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking Riomet and by use of the minimum effective dose of Riomet. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Riomet treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Riomet should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Riomet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Riomet, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, Riomet should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). Riomet should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of Riomet, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking Riomet do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS).
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking Riomet, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS).
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Riomet or any other oral anti-diabetic drug.
Monitoring of renal function — Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Riomet. In patients with advanced age, Riomet should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Riomet should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION).
Before initiation of Riomet therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Riomet discontinued if evidence of renal impairment is present.
Use of concomitant medications that may affect renal function or metformin disposition — Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: Drug Interactions), should be used with caution.
Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) — Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Riomet should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.
Hypoxic states — Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Riomet therapy, the drug should be promptly discontinued.
Surgical procedures — Riomet therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.
Alcohol intake — Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Riomet.
Impaired hepatic function — Since impaired hepatic function has been associated with some cases of lactic acidosis, Riomet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels — In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Riomet and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests).
Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful.
Change in clinical status of patients with previously controlled type 2 diabetes — A patient with type 2 diabetes previously well controlled on Riomet who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Riomet must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).
Hypoglycemia — Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Loss of control of blood glucose — When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Riomet and temporarily administer insulin. Riomet may be reinstituted after the acute episode is resolved.
The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either Riomet or sulfonylurea monotherapy, combined therapy with Riomet and sulfonylurea may result in a response. Should secondary failure occur with combined Riomet/sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.
Patients should be informed of the potential risks and benefits of Riomet and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.
The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue Riomet immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Riomet, gastrointestinal symptoms, which are common during initiation
