Zix Pg

Uses

Aceclofenac is used for the relief of pain and inflammation in both acute and chronic pain like osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, dental pain, post-traumatic pain, low back pain, gynaecological pain etc.

Pregabalin is used for the management of neuropathic pain associated with diabetic peripheral neuropathy and management of post-herpetic neuralgia. It is also used for the adjunctive therapy for adult patients with partial onset seizures. It can be used for the management of fibromyalgia and neuropathic pain associated with spinal cord injury.

Zix Pg is also used to associated treatment for these conditions: Ankylosing Spondylitis (AS), Osteoarthritis (OA), Rheumatoid ArthritisDiabetic Peripheral Neuropathic Pain (DPN), Epilepsies, Fibromyalgia, Generalized Anxiety Disorder (GAD), Neuropathic Pain, Partial-Onset Seizures, Peripheral Neuropathic Pain, Peripheral neuropathy, Postherpetic Neuralgia

How Zix Pg works

Through COX-2 inhibition, aceclofenac downregulates the production of various inflammatory mediators including prostaglandin E2 (PGE2), IL-1β, and TNF from the arachidonic acid (AA) pathway. Inhibition of IL-6 is thought to be mediated by diclofenac converted from aceclofenac . Suppressed action of inflammatory cytokines decreases the production of reactive oxygen species. Aceclofenac is shown to decreased production of nitrous oxide in human articular chondrocytes . In addition, aceclofenac interferes with neutrophil adhesion to endothelium by decreasing the expression of L-selectin (CD62L), which is a cell adhesion molecule expressed on lymphocytes . Aceclofenac is proposed to stimulate the synthesis of glycosaminoglycan in human osteoarthritic cartilage which may be mediated through its inhibitory action on IL-1 production and activity . The chrondroprotective effects are generated by 4'-hydroxyaceclofenac which suppresses IL-1 mediated production of promatrix metalloproteinase-1 and metalloproteinase-3 and interferes with the release of proteoglycan from chrondrocytes .

Although the mechanism of action has not been fully elucidated, studies involving structurally related drugs suggest that presynaptic binding of pregabalin to voltage-gated calcium channels is key to the antiseizure and antinociceptive effects observed in animal models.

By binding presynaptically to the alpha2-delta subunit of voltage-gated calcium channels in the central nervous system, pregabalin modulates the release of several excitatory neurotransmitters including glutamate, substance-P, norepinephrine, and calcitonin gene related peptide. In addition, pregabalin prevents the alpha2-delta subunit from being trafficked from the dorsal root ganglia to the spinal dorsal horn, which may also contribute to the mechanism of action.

Although pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), it does not bind directly to GABA or benzodiazepine receptors.

Dosage

Zix Pg dosage

Adults: The maximum recommended dose is 200 mg daily, taken as two separate 100 mg doses, one tablet in the morning and one in the evening.

Children: There is no clinical data on the use of aceclofenac in children.

Elderly: The pharmacokinetics of aceclofenac are not altered in elderly patients, therefore it is not considered necessary to modify the dose and dose frequency.

Renal insufficiency: There is no evidence that the dosage of aceclofenac needs to be modified in patients with mild renal impairment.

Hepatic insufficiency: The dose of aceclofenac should be reduced in patients with hepatic impairment. An initial daily dose of 100 mg should be administered.

Aceclofenac SR tablet:

The recommended dose is 200 mg once daily.

Neuropathic pain associated with diabetic peripheral neuropathy: The maximum recommended dose of Pregabalin is 100 mg three times a day (300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Dosing should begin at 50 mg three times a day (150 mg/day) and may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

Post-herpetic neuralgia: The recommended dose of Pregabalin is 75 to 150 mg two times a day, or 50 to 100 mg three times a day (150 to 300 mg/day) in patients with creatinine clearance of at least 60 mL/min. Dosing should begin at 75 mg two times a day, or 50 mg three times a day (150 mg/day) and may be increased to 300 mg/day within 1 week based on efficacy and tolerability.

Adjunctive therapy for adult patients with partial onset seizures: Pregabalin at doses of 150 to 600 mg/day has been shown to be effective as adjunctive therapy in the treatment of partial onset seizures in adults. The total daily doseshould be divided and given either two or three times daily. In general, it is recommended that patients be started on a total daily dose no greater than 150 mg/day (75 mg two times a day, or 50 mg three times a day). Based on individual patient response and tolerability, the dose may be increased to a maximum dose of 600 mg/day.

Management of Fibromyalgia: The recommended dose of Pregabalin for fibromyalgia is 300 to 450 mg/day. Dosing should begin at 75 mg two times a day (150 mg/day) and may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability. Patients who do not experience sufficient benefit with 300 mg/day may be further increased to 225 mg two times a day (450 mg/day).

Neuropathic pain associated with spinal cord injury: The recommended dose range is 150 to 600 mg/day. The recommended starting dose is 75 mg two times a day (150 mg/day). The dose may be increased to 150 mg two times a day (300 mg/day) within 1 week based on efficacy and tolerability.

.Patients who do not experience sufficient pain relief after treatment with 300 mg/day and who tolerate pregabalin may be treated with up to 300 mg two times a day. Neurolin® capsules can be taken without regards to meals.

Side Effects

Generally aceclofenac is well tolerated. The majority of side effects observed have been reversible and of a minor nature and include gastrointestinal disorders (dyspepsia, abdominal pain, nausea and diarrhoea) and occasional occurance of dizziness. Dermatological side effects including pruritus and rash. Abnormal hepatic enzyme levels and raised serum creatinine have occasionally been reported.

The most common side effects include dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and abnormal thinking.

Toxicity

Some common adverse effects include gastro-intestinal disorders (dyspepsia, abdominal pain, nausea), rash, ruber, urticaria, symptoms of enuresis, headache, dizziness, and drowsiness . Oral LD50 value in rats is 130 mg/kg .

In a systematic review that included 38 randomized controlled trials, there were 20 identified adverse effects that were significantly associated with pregabalin, most of which involve the central nervous system and cognition. The identified adverse effects include vertigo, dizziness, balance disorder, incoordination, ataxia, blurred vision, diplopia, amblyopia, somnolence, confusional state, tremor, disturbance in attention, abnormal thinking, asthenia, fatigue, euphoria, edema, peripheral edema, dry mouth, and constipation .

The most common symptoms of pregabalin toxicity (dose range includes 800 mg/day and single doses up to 11,500 mg) include somnolence, confusion, restlessness, agitation, depression, affective disorder and seizures.

Since there is no antidote for pregabalin overdose, patients should receive general supportive care. If appropriate, gastric lavage or emesis may help eliminate unabsorbed pregabalin (healthcare providers should take standard precautions to maintain the airway).

Pregabalin pharmacokinetic properties suggest that extra-corporeal elimination methods including haemodialysis, may be useful in situations of severe toxicity. However, there are cases where patients have presented with very high serum levels of pregabalin and have been successfully managed with supportive care alone.

Precaution

Aceclofenac should be administered with caution to patients with symptoms indicative of gastrointestinal disorders, with a history of peptic ulceration, ulcerative colitis, Crohn\'s disease, hepatic porphyria, and coagulation disorders. Patients suffering from severe hepatic impairment must be monitored.

Discontinuation of Pregabalin without tapering may produce insomnia, nausea, headache and diarrhea. So it should be tapered gradually over a minimum of 1 week rather than discontinued abruptly. Creatinine kinase may be elevated if treated with Pregabalin. It should be discontinued rapidly if myopathy is diagnosed or suspected or if creatinine kinase is elevated markedly.

Interaction

Lithium and Digoxin: Aceclofenac, like many NSAIDs may increase plasma concentrations of lithium and Digoxin.

Diuretics: Aceclofenac, like other NSAIDs, may interact the activity of diuretics.

Anticoagulants: Like other NSAIDs, Aceclofenac may enhance the activity of anticoagulant. Close monitoring of patients on combined anticoagulants and Aceclofenac therapy should be undertaken.

Methotrexate: Caution should be exercised if NSAIDs and Methotrexate are administered within 24 hours of each other, since NSAIDs may increase Methotrexate plasma levels, resulting in increased toxicity.

Volume of Distribution

The volume of distribution is approximately 25 L .

After oral administration of pregabalin, the reported apparent volume of distribution is roughly 0.5 L/kg.

Although pregabalin is not very lipophilic, it is able to cross the blood brain barrier(BBB). System L transporters facilitate the transport of large amino acids across the BBB and it has been confirmed that pregabalin is a substrate. This information suggests that system L transporters are responsible for pregabalin uptake into the BBB.

In rat models, pregabalin has been shown to cross the placenta.

Elimination Route

Aceclofenac is rapidly and completely absorbed from the gastrointestinal tract and circulates mainly as unchanged drug following oral administration. Peak plasma concentrations are reached around 1.25 to 3 hours post-ingestion, and the drug penetrates into the synovial fluid where the concentration may reach up to 60% of that in the plasma . There is no accumulation in regular dosing, with similar maximum plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax) after single and multiple doses .

After oral dosing administered in the fasted state, pregabalin absorption is rapid, and extensive. Pregabalin oral bioavailability is reported to be ≥90% regardless of the dose. Cmax is attained within 1.5 hours after single or multiple doses, and steady state is attained within 24-48 hours with repeated administration. Both Cmax and AUC appear to be dose proportional.

Food decreases the rate of pregabalin absorption and as a result, lowers the Cmax by an estimated 25-30% and increases the Tmax to approximately 3 hours. However, the effect of food does not appear to impact the total absorption of pregabalin in a way that is clinically relevant. As a result, pregabalin can be administered with or without food.

Half Life

The mean plasma elimination half-life is approximately 4 hours .

The elimination half life of pregabalin is 6.3 hours.

Clearance

The mean clearance rate is approximately 5 L/h .

In young healthy subjects the mean renal clearance is estimated to be 67.0 to 80.9 mL mL/min. Given pregabalin's lack of plasma protein binding, this clearance rate suggests that renal tubular reabsorption is involved.

Elimination Route

The main route of elimination is via the urine where the elimination accounts for 70-80% of clearance of the drug . Approximately two thirds of the administered dose is excreted via the urine, mainly as glucuronidated and hydroxylated forms of aceclofenac . About 20% of the dose is excreted into feces .

Pregabalin is almost exclusively eliminated in the urine.

Further, based on preclinical studies, pregabalin does not appear to undergo racemization to the R enantiomer in the body.

Pregnancy & Breastfeeding use

Pregnancy: There is no information on the use of aceclofenac during pregnancy. Aceclofenac should not be administered during pregnancy, unless there are compelling reasons for doing so. The lowest effective dose should be administered.

Lactation: There is no information on the secretion of aceclofenac in breast milk. The use of aceclofenac should therefore be avoided during lactation unless the potential benefits to the mother outweigh the possible risks to the children.

Pregnancy category C. So it should only used if potential benefit justifies the potential risks to the fetus.

Nursing mother: It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. So it should be used in nursing mother only if there is a clear benefit over the risk.

Contraindication

Aceclofenac should not be administered to patients with active or suspected peptic ulcer or gastro-intestinal bleeding. It should not be given to patients with moderate to severe renal impairment. Close medical surveillance is also imperative in patients suffering from severe impairment of hepatic function. It should not be prescribed during pregnancy, unless there are compelling reasons for doing so. The lowest effective dosage should be used. Aceclofenac should not be administered to patients previously sensitive to Aceclofenac or in whom aspirin or NSAIDs precipitate attacks of asthma, acute rhinitis or urticaria or who are hypersensitive to these drugs.

Pregabalin is contraindicated in patients with known hypersensitivity to Pregabalin or any of its components.

Special Warning

Use in children & adolescents: The safety and effectiveness of Pregabalin have not been established in patients below the age of 18 years.

Use in elderly (Over 65 years of age): No dosage adjustment is necessary in elderly patients. Overdose: In overdoses up to 15 g, no unexpected adverse effects were reported.

Paediatric use: The safety and efficacy of pregabalin in paediatric patients have not been established.

Acute Overdose

There is no human data available on the consequences of aceclofenac overdosage. After overdosage, following therapeutic measures to be taken: absorption should be prevented as soon as possible by means of gastric lavage and treatment with activated charcoal. Supportive and symptomatic treatment should be given for complications.

Storage Condition

Keep at a cool and dry place, protected from light and moisture.

Store at a cool & dry place, protected from light and moisture. Keep out of reach of the children.

Innovators Monograph

You find simplified version here Zix Pg