Gapeam Budibac

Uses

Baclofen is used for:

• Spasm.
• Spinal cord diseases.
• Cerebrovascular accidents or neoplastic or degenerative brain disease.
• Muscle spasm of cerebral origin especially infantile cerebral palsy.
• The alleviation of spasticity resulting from multiple sclerosis

Gabapentin is used for-

• Epilepsy
• Neuropathic pain (e.g. postherpetic neuralgia) and other pain conditions
• Bipolar disorder
• Headache syndrome
• Spasticity in multiple sclerosis and spinal cord diseases

Others indication are:

• Alcohol withdrawal
• Schizoaffective disorder
• Post-traumatic stress disorder
• Agitation and behavioural disturbances
• associated with dementia
• Lesch-Nyhan syndrome
• Essential tremor
• Restless legs syndrome
• Brachioradial pruritus
• Hemichorea/hemiballismus
• Hot Flashes

Pentoxifylline is used for the treatment of peripheral vascular disease evident as intermittent claudication, venous leg ulcers, Pentoxifylline can improve function and symptoms but is not intended to replace more definitive therapy, such as surgical bypass, or removal of arterial obstructions when treating peripheral vascular disease.

Gapeam Budibac is also used to associated treatment for these conditions: Joint Pain, Soreness, Muscle, Flexor spasm, Reversible Spasticity, Severe cerebral origin Spasticity, Severe spinal cord origin SpasticityPartial-Onset Seizures, Peripheral Neuropathic Pain, Postherpetic NeuralgiaIntermittent Claudication, Venous Leg Ulcer (VLU), Severe alcoholic liver disease

How Gapeam Budibac works

The exact mechanism of action of baclofen is not fully understood at this time , . Many studies indicate that baclofen is a GABA-B receptor agonist , , , , . Despite this, there is no conclusive evidence that the effects of baclofen on GABA systems are involved in the production of its clinical effects .

Baclofen is an effective and widely used antispastic agent with a spinal site of action. Its mechanism of action and pharmacological properties are different from the effects of other antispastic agents. In addition, baclofen has central sites of action, shown by its adverse event profile and general CNS depressant properties . GABA-B receptors interact with signal transduction pathways and neurotransmitter systems. Baclofen exerts an antinociceptive effect. The clinical significance of this warrants further research data for clarification.

Baclofen depresses monosynaptic and polysynaptic reflex transmission, by various actions, and possibly including the stimulation of GABAβ-receptors. This stimulation results in the inhibition of excitatory neurotransmitter (glutamate and aspartate) release, which may normally contribute to pain and spasticity. Although baclofen is an analog of the inhibitory neurotransmitter gamma-amino-butyric acid (GABA), there are no conclusive data indicating GABA systems are involved in its clinical effects .

The precise mechanism through which gabapentin exerts its therapeutic effects is unclear. The primary mode of action appears to be at the auxillary α2δ-1 subunit of voltage-gated calcium channels (though a low affinity for the α2δ-2 subunit has also been reported). The major function of these subunits is to facilitate the movement of pore-forming α1 subunits of calcium channels from the endoplasmic reticulum to the cell membrane of pre-synaptic neurons. There is evidence that chronic pain states can cause an increase in the expression of α2δ subunits and that these changes correlate with hyperalgesia. Gabapentin appears to inhibit the action of α2δ-1 subunits, thus decreasing the density of pre-synaptic voltage-gated calcium channels and subsequent release of excitatory neurotransmitters. It is likely that this inhibition is also responsible for the anti-epileptic action of gabapentin.

There is some evidence that gabapentin also acts on adenosine receptors and voltage-gated potassium channels, though the clinical relevance of its action at these sites is unclear.

Patients with peripheral arterial disease (PAD) may suffer from intermittent claudication, exertional leg pain that resolves upon rest, which is underscored by a complex etiology including vascular dysfunction (reduced limb perfusion, angiogenesis, and microcirculatory flow), systemic inflammation, and skeletal muscle dysfunction. Pentoxifylline (PTX), (3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione) or 1-(5-oxohexyl)-3,7-­dimethylxanthine, is a methyl-xanthine derivative that acts to lower blood viscosity by increasing erythrocyte flexibility, reducing plasma fibrinogen, inhibiting neutrophil activation, and suppressing erythrocyte/platelet aggregation; it also has antioxidant and anti-inflammatory effects. Although the precise mechanism of action has yet to be elucidated, numerous studies have suggested several effects of PTX.

The classical interpretation of PTX's broad effects is due to its ability to act, in vitro, as a non-specific cyclic-3',5'-phosphodiesterase (PDE) inhibitor at millimolar concentrations; specifically, it has been proposed that inhibition of PDE type III and IV isozymes leads to elevated cyclic adenosine monophosphate (cAMP) levels, which mediate diverse downstream effects. This view has been challenged, specifically by observing those plasma concentrations of PTX in routine clinical use are typically only around 1μM, far lower than those used to inhibit PDEs in vitro. Instead, several studies have suggested that PTX can modulate adenosine receptor function, specifically the Gα-coupled A2A receptor (A2AR). Whether PTX acts directly as an A2AR agonist is unclear, although it can clearly increase the response of A2AR to adenosine. A2AR activation activates adenylyl cyclase, which increases intracellular cAMP levels; this observation may explain PTX's ability to increase intracellular cAMP in a PDE-independent fashion.

Elevated cAMP levels have numerous downstream effects. cAMP-mediated activation of protein kinase A (PKA) suppresses nuclear translocation of NF-κB, which suppresses transcription of pro-inflammatory cytokines such as tumour necrosis factor (TNF-α), interleukin-1 (IL-1), and IL-6 as well as TNF-induced molecules such as adhesion molecules (ICAM1 and VCAM1) and the C-reactive protein (CRP). PTX has also been shown to prevent the downstream phosphorylation of p38 MAPK and ERK, which are responsible for assembling the NADPH oxidase involved in the neutrophil oxidative burst. This effect is due to a PKA-independent decrease in Akt phosphorylation and a PKA-dependent decrease in phosphorylation of p38 MAPK and ERK. This transcriptional regulation at least partially explains the anti-inflammatory and anti-oxidative properties of PTX.

Also, activated PKA can activate the cAMP response element-binding protein (CREB), which itself blocks SMAD-driven gene transcription, effectively disrupting transforming growth factor (TGF-β1) signalling. This results in lower levels of fibrinogenic molecules such as collagens, fibronectin, connective tissue growth factor, and alpha-smooth muscle actin. Hence, disruption of TGF-β1 signalling may explain the anti-fibrotic effects of PTX, including at least some of the decrease in blood viscosity.

The picture is complicated by the observation that PTX metabolites M1, M4, and M5 have been shown to inhibit C5 Des Arg- and formyl-methionylleucylphenylalanine-induced superoxide production in neutrophils and M1 and M5 significantly contribute to PTX's observed hemorheological effects. Overall, PTX administration is associated with decreased pro-inflammatory molecules, an increase in anti-inflammatory molecules such as IL-10, and decreased production of fibrinogenic and cellular adhesion molecules.

Dosage

Gapeam Budibac dosage

Adults:

Treatment should be started with low dose and increased gradually until optimum effect is achieved. The following dosage titration schedule is suggested:

5 mg 3 times daily for 3 days,

10 mg 3 times daily for 3 days,

15 mg 3 times daily for 3 days,

20 mg 3 times daily for 3 days,

25 mg 3 times daily for 3 days.

Thereafter, additional increases may be necessary. The optimum dosage generally ranges from 30 - 80 mg daily in 3 - 4 divided doses. Daily doses of 100 - 120 mg may be given to carefully supervised patients in hospitals.

Children:

Treatment should be started at a very low dose, e.g., 0.3 mg/kg per day in divided (preferably 4) doses. The dosage should be raised cautiously at 1-2 week intervals until it is sufficient for the child\'s individual needs. The usual dosage range for maintenance therapy is 0.75 to 2 mg/kg body weight per day. In children aged over 10 years a maximum daily dose of 2.5 mg/kg body weight may be given.

Renal Insufficiency:

Baclofen is excreted principally in urine as unchanged drug. So it may be necessary to reduce the dosage in patients with impaired renal function.

Neuropathic pain: 300 mg on day-1, then 300 mg twice on day-2, then 300 mg thrice on day-3, then increase the dose according to response in steps of 300 mg daily to maximum 1800 mg daily in three divided doses.

Partial seizure/epilepsy: 300 mg on day-1, then 300 mg twice on day-2, then 300 mg thrice on day-3, then increase the dose according to response in steps of 300 mg daily to maximum 2400 mg daily in three divided doses.

In case of children:

• For 3-12 years: 10 to 15 mg/kg, Incase of titration 25-35 mg/kg daily in 3 divided doses.
• Maintenance dose is 900 mg daily (body weight 26-36 Kg) or 1.2 gm daily (body weight 37-50 Kg).

The usual dosage of Pentoxifylline tablet is one tablet (400 mg) two to three times a day with meals. While the effect of Pentoxifylline tablet may be seen within 2 to 4 weeks, it is recommended that treatment be continued for at least 8 weeks.

Digestive and central nervous system side effects are dose related. If patients develop these effects it is recommended that the dosage be lowered to one tablet twice a day (800 mg/day). If side effects persist at this lower dosage, the administration of Pentoxifylline tablet should be discontinued.

Gabapentin can be taken orally with or without food.

Side Effects

The most common side effects include drowsiness, nausea, dizziness, lassitude, lightheadedness, confusion, fatigue, muscular pain & weakness and hypotension.

Generally Gabapentin is well tolerated but a few side effects like fatigue, dizziness , ataxia, weight gain, peripheral edema, dry mouth and somnolence, may occur. Rarely it may cause fulminate hepatic failure, or aplasticanemia.

Cardiovascular- dyspnea, edema, hypotension.

Digestive- anorexia, cholecystitis, constipation, dry mouth/thirst.

Nervous- anxiety, confusion, depression, seizures.

Respiratory- epistaxis, flu-like symptoms, laryngitis, nasal congestion.

Skin and Appendages- brittle fingernails, pruritus, rash, urticaria, angioedema.

Special Senses- blurred vision, conjunctivitis, earache, scotoma.

Miscellaneous- bad taste, excessive salivation, leukopenia, malaise, sore throat/swollen neck glands, weight change.

Toxicity

LD50 after oral administration in rats: 145 mg/kg

Overdosage: Vomiting, muscular hypotonia, drowsiness, accommodation disorders, coma, respiratory depression, and seizures may occur with overdosage .

Pregnancy: This drug is a pregnancy category C drug. There are no adequate and well-controlled studies that have been performed with pregnant women. Baclofen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus .

Excretion in breastmilk: It is unknown whether this drug is excreted in human breast milk. Because many drugs are excreted in human milk, caution is warranted when baclofen is administered to a nursing woman .

The oral TDLo of gabapentin in humans is 2.86 mg/kg and the LD₅₀ in rats has been found to be >8000 mg/kg. Symptoms of overdose are consistent with the drug's adverse effect profile and involve CNS depression (e.g. dizziness, drowsiness, slurred speech, lethargy, loss of consciousness) and gastrointestinal symptoms such as diarrhea. Management of overdose should involve symptomatic and supportive treatment. Gabapentin can be removed by hemodialysis - this may be of benefit in some patients, such as those with impaired renal function.

Multi-drug overdoses involving gabapentin, particularly in combination with other CNS depressants such as opioids, can result in coma and death - this possibility should be considered when managing overdosage.

Overdoses of pentoxifylline have been reported with symptoms including agitation, fever, flushing, hypotension, convulsions, somnolence, and loss of consciousness beginning 4-5 hours following ingestion and lasting up to 12 hours. Symptomatic treatment is recommended, specifically pertaining to maintaining proper respiration, blood pressure, and controlling convulsions. Activated charcoal may prove useful in absorbing excess pentoxifylline in overdose cases. Patients have recovered from overdose even at doses as high as 80 mg/kg.

Precaution

Patients suffering from psychotic disorders, schizophrenia, depressive or manic disorders, confusional states or Parkinson\'s disease, should be treated cautiously with Baclofen. Baclofen stimulates gastric acid secretion and should be used with caution in patients with a history of peptic ulcer and avoided in those with active peptic ulcer disease . Liver function should be monitored in patients with liver disease; patients with renal impairment need a reduced dose. Baclofen should be used with caution in patients with respiratory impairment. Observations of increased blood sugar concentrations suggest caution in patients with diabetes mellitus. Care is also required in the elderly, in whom adverse effects may be more common, and in patients with cerebrovascular disease (who tolerate Baclofen poorly). Baclofen may cause drowsiness; patients affected should not drive or operate machinery. Abrupt withdrawal of Baclofen may result in a withdrawal syndrome and exacerbation of spasticity; dosage should be reduced gradually over at least 1 to 2 weeks, or longer if symptoms occur.

Patients should be instructed to take Gabapentin only as prescribed. While using Gabapentin patients should be instructed either not to drive a car or to operate other complex machinery until they have gained sufficient experiences about Gabapentin whether or not it affects their mental and/or motor performance adversely.

Patients on warfarin should have frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration, cerebral and/or retinal bleeding) should have periodic examinations for bleeding including, hematocrit and/or hemoglobin.

Interaction

Alcohol and other CNS depressants may exacerbate the CNS effects of Baclofen and should be avoided. There may be increased weakness if Baclofen is given to patients taking a tricyclic antidepressant and an increased hypotensive effect if it is given to patients receiving antihypertensive therapy.

Antacids may reduce the bioavailability of Gabapentin by up to 20%. Cimetidine may alter its reanal excretion. Gabapentin does not interact with other anti-epileptic drug or with oral contraceptive preparations.

Patients on warfarin should have frequent monitoring of prothrombin times, while patients with other risk factors complicated by hemorrhage (e.g., recent surgery, peptic ulceration) should have periodic examinations for bleeding including hematocrit and/or hemoglobin. Concomitant administration of Pentoxifylline and theophylline-containing drugs leads to increased theophylline levels and theophylline toxicity in some individuals. Such patients should be closely monitored for signs of toxicity and have their theophylline dosage adjusted as necessary. Pentoxifylline has been used concurrently with antihypertensive drugs, beta blockers, digitalis, diuretics, antidiabetic agents, and antiarrhythmics, without observed problems. Small decreases in blood pressure have been observed in some patients treated with Pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensive therapy. If indicated, dosage of the antihypertensive agents should be reduced.

Volume of Distribution

Apparent volume of distribution: 59 liters .

Baclofen does not readily cross the blood-brain barrier .

The apparent volume of distribution of gabapentin after IV administration is 58±6 L. The drug is found in the CSF in concentrations approximately 9-20% of the corresponding plasma concentrations and is secreted into breast milk in concentrations similar to that seen in plasma.

Pentoxifylline has a volume of distribution of 4.15 ± 0.85 following a single intravenous 100 mg dose in healthy subjects.

Elimination Route

Rapidly and almost completely absorbed from the gastrointestinal tract. Absorption may be dose-dependent, being reduced with increased doses .

Baclofen, when introduced directly into the intrathecal space, allows for effective CSF concentrations to be achieved with resulting plasma concentrations 100 times less than concentrations occurring with oral administration , .

Absorption of gabapentin is thought to occur solely via facilitated transport by the LAT1 transporter within the intestines. As this process is saturable, the oral bioavailability of gabapentin is inversely proportional to the administered dose - the oral bioavailability of a 900mg/day regimen is approximately 60%, whereas a 4800mg/day regimen results in only 27% bioavailability. The T_max of gabapentin has been estimated to be 2-3 hours. Food has no appreciable effect on gabapentin absorption.

Oral pentoxifylline (PTX) is almost completely absorbed but has low bioavailability of 20-30% due to extensive first-pass metabolism; three of the seven known metabolites, M1, M4, and M5 are present in plasma and appear soon after dosing. Single oral doses of 100, 200, and 400 mg of pentoxifylline in healthy males produced a mean t_max of 0.29-0.41 h, a mean C_max of 272-1607 ng/mL, and a mean AUC_0-∞ of 193-1229 ng*h/mL; corresponding ranges for metabolites 1, 4, and 5 were 0.72-1.15, 114-2753, and 189-7057. Single administration of a 400 mg extended-release tablet resulted in a heightened t_max of 2.08 ± 1.16 h, lowered C_max of 55.33 ± 22.04 ng/mL, and a comparable AUC_0-t of 516 ± 165 ng*h/mL; all these parameters were increased in cirrhotic patients.

Smoking was associated with a decrease in the C_max and AUC_steady-state of metabolite M1 but did not dramatically affect the pharmacokinetic parameters of pentoxifylline or other measured metabolites. Renal impairment increases the mean C_max, AUC, and ratio to parent compound AUC of metabolites M4 and M5, but has no significant effect on PTX or M1 pharmacokinetics. Finally, similar to cirrhotic patients, the C_max and t_max of PTX and its metabolites are increased in patients with varying degrees of chronic heart failure.

Overall, metabolites M1 and M5 exhibit plasma concentrations roughly five and eight times greater than PTX, respectively. PTX and M1 pharmacokinetics are approximately dose-dependent, while those of M5 are not. Food intake before PTX ingestion delays time to peak plasma concentrations but not overall absorption. Extended-release forms of PTX extend the t_max to between two and four hours but also serves to ameliorate peaks and troughs in plasma concentration over time.

Half Life

Elimination half-life: Approximately 5.5 hours .

The elimination t_1/2 of gabapentin in patients with normal renal function is 5-7 hours. In patients with reduced renal function, the elimination t_1/2 may be prolonged - in patients with a creatinine clearance of 16,17

Overall, pentoxifylline has an elimination half-life of between 0.39 and 0.84 hours, while its primary metabolites have elimination half-lives of between 0.96 and 1.61 hours.

Clearance

Total systemic clearance: 180 mL/min Renal clearance: 103 mL/min

Baclofen is primarily excreted unchanged by the kidneys. It should be administered cautiously, and it may be necessary to reduce the dosage in patients with reduced renal function .

Both the plasma clearance and renal clearance of gabapentin are directly proportional to the patient's creatinine clearance due to its primarily renal elimination.

Pentoxifylline given as a single 100 mg intravenous infusion has a clearance of 3.62 ± 0.75 L/h/kg in healthy subjects, which decreased to 1.44 ± 0.46 L/h/kg in cirrhotic patients. In another study, the apparent clearance of either 300 or 600 mg of pentoxifylline given intravenously (median and range) was 4.2 (2.8-6.3) and 4.1 (2.3-4.6) L/min, respectively. It is important to note that, due to the reversible extra-hepatic metabolism of the parent compound and metabolite 1, the true clearance of pentoxifylline may be even higher than the measured values.

Elimination Route

Baclofen is rapidly and extensively eliminated from the body. There is significant intersubject variation in elimination rates. Baclofen is excreted mainly by the kidney as unchanged drug. Seventy to eighty (70 - 80%) of a dose is measured in the urine as unchanged drug. The remainder of the dose is excreted as unchanged drug in the feces or as metabolites in the urine and feces. Excretion is complete within 72 hours after administration .

Gabapentin is eliminated solely in the urine as unchanged drug. Cimetidine, an inhibitor of renal tubular secretion, reduces clearance by approximately 12%, suggesting that some degree of tubular secretion is involved in the renal elimination of gabapentin.

Pentoxifylline is eliminated almost entirely in the urine and predominantly as M5, which accounts for between 57 and 65 percent of the administered dose. Smaller amounts of M4 are recovered, while M1 and the parent compound account for less than 1% of the recovered dose. The fecal route accounts for less than 4% of the administered dose.

Pregnancy & Breastfeeding use

There are no adequate and well controlled studies of Baclofen in pregnant women. So it should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Baclofen is excreted in breast milk. However, evidence suggests that the quantities are so small that no undesirable effect on the infant would be expected.

Pregnancy: Gabapentin is a pregnancy category C drug; it should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: Gabapentin may be secreted through the breast milk like many other drugs , so it should be used in women who are nursing, only if the benefits clearly outweigh the risks.

Pentoxifylline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pentoxifylline and its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for pentoxifylline in rats, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Baclofen is contraindicated in patients with hypersensitivity to any component of this product.

Gabapentin is contraindicated in patients who have known hypersensitivity to the drug.

Pentoxifylline should not be used in patients with recent cerebral and/or retinal hemorrhage or in patients who have previously exhibited intolerance to this product or methylxanthines such as caffeine, theophylline, and theobromine.

Special Warning

Renal Insufficiency: Baclofen is excreted principally in urine as unchanged drug. So it may be necessary to reduce the dosage in patients with impaired renal function.

Use in Children: Safety and effectiveness of Gabapentin in the management of neuropathic pain in pediatric patients have not been established. Safety and effectiveness of Gabapentin in the management of seizures in pediatric patients below the age of 3 years have not been established.

Renal impaired patient: In case of renal impaired patient Gabapentin doses must be reduced :

• CrCl >60 ml/min: 1200 mg/daily in 3 divided doses
• CrCl 30-60 ml/min: 600 mg/daily in 2 divided doses
• CrCl 15-30 ml/min: 300 mg/daily single dose
• CrCl <15 ml/min: 150 mg/daily single dose or 300 mg/every alternate day
• Heamodialysis: maximum 300 mg after each dialysis Gabapentin can be taken orally with or without food.

Pediatric use: Safety and effectiveness in pediatric patients have not been established.

Acute Overdose

Prominent features are signs of central nervous system depression. No specific antidote of Baclofen is known. Elimination of the agent from GI tract, artificial respiration, administration of fluid with a diuretic and dialysis should be considered.

Overdosage with Pentoxifylline has been reported in children and adults. Symptoms appear to be dose related. Flushing, hypotension, convulsions, somnolence, loss of consciousness, fever, and agitation occurred. In addition to symptomatic treatment special attention must be given to supporting respiration, maintaining systemic blood pressure, and controlling convulsions. Activated charcoal has been used to absorb Pentoxifylline in patients who have overdosed.

Storage Condition

Store in cool & dry place, away from children.

Tablets should be stored below 25° C and protected from light & moisture

Store in a cool and dry place, away from light. Keep out of reach of children.

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