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Cetapin® XR

Second generation - Metformin

1,1-Dimethylbiguanide
Rarely produces lactic acidosis except under predisposing conditions
Approved in US 1995

Metformin: MOA

Antihyperglycaemic

  • Correct elevated hepatic glucose output
    • Inhibits gluconeogenesis from substrates like lactate, pyruvate, glycerol and aminoacids
      Inhibits glycogenolysis
  • Opposes gluconeogenic actions of glucagon
  • Enhances the glucose transport activity of insulin in muscles and glycogen and lipid synthesis
  • Decrease intestinal absorption of glucose
  • Does not increase insulin secretion
    • Not hypoglycaemic, even at high doses

Clinical effects

  • Decreases FBG by 25 to 30%
  • Decreases A1c by 1 to 2 %
  • Improves the response of muscle to insulin
  • Weight neutral or weight reduction
  • Lipid profile improves

Cardio protective effects

Multicentre Metformin study group

  • Two protocols
    • First: 289 moderately obese T2DM inadequately controlled by diet (M = 143. Pl = 146 pts)
      - Metformin lowered FBG (53mg/dl vs 6.3mg/dl) and A1c (1.4% vs 0.4%) vs placebo
    • Second: 632 patients not controlled by diet & Max Glibenclamide
      -Combination MG (213) > M or G (209) alone
      - Metformin did not cause increase in lactate concentrations or increase insulin concentration or cause hypoglycaemia

Metformin monotherapy is well tolerated and improves glycaemic control & lipid concentrations in pts with NIDDM

Metabolic effects of Metformin in NIDDM

(Obese pts with NIDDM, isotope dilution, indirect calorimetry, etc..)

  1. Metabolic effects of M were to inhibit gluconeogenesis, reduce hepatic glucose output and lower FBG
  2. Lower FBG sets the stage for better glycaemic control throughout the day

Metformin acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis. It also seems to induce weight loss preferentialy involving adipose tissue.

COSMIC study

  1. Comparative Outcomes Study of Metformin Intervention versus Conventional
  2. M grp 7227 and usual care: 1,505 patients
  3. 500 mg bid with meals, increased weekly
  4. Incidence of SAE similar (10.3%m vs 11.0% usual care)
  5. Lactic acidosis was not observed
  6. Metformin safely prescribed, if taken care of contraindications and warnings

Metformin safety

  • Epidemiological data from countries with more than 10 years of use suggest a smaller risk of lactic acidosis with Metformin
    3 per 100,000 patient years
  • Phenformin : 64 per 100,000 patient years

MALA Study: Metformin Associated Lactic Acidosis Study
Except elderly and with renal insufficiency it was safe

UKPDS

 On balance, Metformin treatment would appear to be advantageous as primary pharmacological therapy in diet-treated overweight patients

International Diabetes Federation, 2005. Clinical Guidelines Task Force

  • Metformin remains the drug of choice for first-line therapy.
  • It can be used along with all the anti-diabetic molecules currently available in the market.

Comprehensive care section

Metformin profile

Best studied agent for treatment of diabetes

  • Not associated with weight gain
  • Reduced cardiovascular events
  • For overweight patients in UKPDS
  • Not associated with hypoglycaemia risk

 

Metformin common side effects

  • Decreased appetite
  • Nausea and
  • Diarrhoea
    • Symptoms abate with time
    • Or reduction of dose
    • Discontinuation in 3% to 5% patients

IR side effects

Immediate release (IR) formulation transits rapidly through the digestive system.

IR tablet rapidly dissolves and the drug moves too quickly through the gastrointestinal system before complete absorption takes place.

This often causes a disturbance in the colon resulting in side effects such as diarrhoea, flatulence.

Metformin properties

Unique

  • Available as hydrochloride salt
  • Very high water solubility (>300 mg/mL)
  • Absorption exclusively in upper GI Tract
  • Poor permeability in lower GI Tract

Metformin absorption

OCTs are a family of polyspecific organic cation transporters responsible, at least in part, for the uptake of organic cations, including xenobiotics and endogenous compounds from the systemic circulation, maintaining body fluid homeostasis and acting as a defense system against toxic agents.
Oct-1 localisation in the basolateral membrane in the liver may explain its possible function as an uptake mechanism for organic cations

Metformin: improvement

  • Multiple doses of lesser dosage
  • Desirable dosage form: Extended gastric residence
  • Resistance to pattern of waves of motility in GIT
  • Gradual release ensuring effective absorption

Rationale for XR

  • Polypharmacy is common in the T2DM population
  • Complex regimens lead to suboptimal compliance
  • Compliance reduces when the daily dosage frequency or the number of treatments administered increases
  • A once-daily formulation of Metformin provides an effective and well-tolerated option

XR formulations difficulties

  • Absorption limited to upper GIT
    • Labelled as "Absorption Window"
  • High unit dose of 500 mg per tablet
  • Poor absorption in distal small intestine, large intestine and colon
  • GIT movements

Multiple polymer hydrophilic matrix technology

  • One of the best possible technology with polymers
  • Polymer wetting, Polymer hydration
  • Gel formation, Swelling thus gastric retention
  • Polymer dissolution
    • Drug release determined by diffusion through gel and by rate of tablet erosion
    • Maximum drug available at site of absorption

Extended release advantages

Improved bioavailability
Releases Metformin at a rate likely to provide the desired plasma levels of drug for an extended time period
Ensures a complete release during transit from stomach to jejunum.
Possible due to technology that has extended residence time in the upper gastrointestinal tract,

XR over IR

Switching patients from IR Metformin to Metformin-XR -> halving of the incidence of any gastrointestinal side effect, or of diarrhoea.
Similarly, among new patients the incidences of these side effects in the IR Metformin group were almost twice those in the Metformin-XR group.

Metformin XR has potential to improve the convenience and tolerability of Metformin based therapy

Reason for BE

Pharmacodynamic action is related to plasma concentration.
Bioequivalence of products is most important to assure equal therapeutic efficacy.
BE confirms usage of new formulation as therapeutic alternative to the reference formulation

Conclusion of BE report

Cetapin® XR 500 mg tablets and International XR 500 mg tablets meet the 80-125% bioequivalence criteria for AUC and C max parameters.

They are Bioequivalent.

Metformin XR summary

  • Good antihyperglycaemic effect
  • Positive influence on a variety of cardiovascular risk factors
  • Optimal first line therapy for patients with Type 2 diabetes - barring any contraindications to its use
  • Improve convenience and tolerability of Metformin

Pharmacokinetics

Metformin

  • Poorly metabolised
  • Excreted unchanged in urine
  • Binds poorly to mitochondrial membranes
  • Bioavailability is 50 to 60%

Organic cationic transporter (OCT)

Biguanide compounds are positively charged (cationic) at physiological pH
OCT-1 is responsible for intestinal uptake and hepatic uptake.

Absorption and distribution

  • C Max of 7 hours: Range 4 to 8 hours
  • Extent of absorption similar to IR
  • Extent of absorption improved with food, but no effect of food on C max and T max
  • Negligibly bound to plasma proteins
  • Steady state concentration in 24 to 48 hrs
    • No accumulation on repeated doses

Metabolism and elimination

  • Does not undergo hepatic metabolism nor biliary excretion
  • Excreted unchanged in urine
  • Renal clearance is 3.5 times greater than creatinine clearance
  • 90% excreted renally within 24 hours
  • Tubular secretion is major process

Special populations

  • The pharmacokinetics of Cetapin® XR in T2DM pts comparable to normal healthy volunteers
  • Pregnancy : Cetapin® XR is not recommended for use in pregnancy.
  • Paediatrics - Safety and effectiveness has not been established
  • Elderly: Initial and maintenance dosing of Cetapin® XR should be conservative
  • Surgical procedures: Temporarily suspended for any surgical procedure

Side effects of Metformin

  • Gastrointestinal
    • Abdominal discomfort
    • Anorexia
    • Diarrhoea
    • Flatulence
      • Incidence much less with XR

Lactic acidosis

The most widely publicised adverse effect of biguanide therapy
In clinical settings of increased lactate production or reduced lactate clearance, such as liver disease, renal dysfunction or other illness causing tissue hypoxia, especially cardiac or respiratory dysfunction, use of biguanides may provoke lactic acidosis
Incidence of lactic acidosis was clearly much greater with Phenformin than with Metformin, being about 10-15 times higher

Metformin causes little or no rise in plasma lactate levels.

Contraindications

  • Significant Renal disease (Sr. Creat >1.4 F, 1.5 mg/dL for M)
  • Known hypersensitivity to Metformin
  • Hepatic failure
  • Congestive heart failure
  • Acute or chronic metabolic acidosis

Temporary discontinuation

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.

Drug interactions

  • Cimetidine reduces renal clearance
  • Alpha glucosidase inhibitor: reduction in bioavailability
  • Drugs causing hyperglycaemia
    • Thiazides
    • Estrogen
    • Corticosteroids
    • Thyroid products
    • Sympathomimetics
    • CCB
    • Phenytoin
    • Oral contraceptives

Indications

As an adjunct to diet and exercise to improve glycaemic control in patients with T2DM

Dosage

  • Individualised on basis of effectiveness and tolerance not exceeding max. recommended dose
  • Given once daily with evening meal
  • Start at low dose with gradual dose escalation
  • Start with: 500 mg OD and increase with 500 mg on weekly basis up to maximum of 2000 mg
  • Must be swallowed whole and never crushed or chewed

Metformin and alcohol

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 Cetapin® XR.

In combination with insulin

  • The addition of Metformin to insulin therapy resulted in haemoglobin A1c concentrations that were 10% lower than those achieved by insulin therapy alone.
  • This improvement in glycaemic control occurred with the use of 29% less insulin and without significant weight gain.
  • Metformin is an effective adjunct to insulin therapy in patients with Type 2 diabetes.

References

Met formin: An update; Ann Int Med 2002;25-33
JAPI, Ann Int Med, ADA, NEJM, Drugs
DeFronzo et al NEJM Vol.333, 1995;541-9
Stumvoli et al NEJM 1995; 333;550-4
Diabetes Care 2005
Diabetes Care, 25, 2002, 2133-40
Crofford O B, NEJM 1995; 333;588-9
Joshi SR ;JAPI vol 53, Nov 2005:963-72
Book on Medical Mgmt of T2DM, ADA, 2004
Vidon et al Diabetes Res Clin Pract. 1988 Feb 19;4(3):223-9
Joshi SR ;JAPI vol 53, Nov 2005:963-72
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, JPET 302:510-515, 2002
Blonde et al Curr Med Res Opin, 2004;565-72
Blonde et al Curr Med Res Opin, 2004;565-72
Our BE Report: Data on File
Pharmacol Rev 55:425-461, 2003
Larissa Avile´s-Santa,et al Ann Intern Med. 1999;131:182-188
See Kemp et al. AMP-activated protein kinase, super metabolic regulator.Biochem Soc Trans 2003 Feb;31(Pt 1):162-8

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