Allopathy
Prescription Required
DCGI (Drugs Controller General of India)
Schedule H
Paracetamol + Ibuprofen is available in the form Oral Tablet, Suspension
Paracetamol + Ibuprofen Tablet is taken orally, usually 3 times daily.
Paracetamol and ibuprofen block enzymes the body needs to make prostaglandins. These are known as COX enzymes. While Paracetamol only works in the brain, ibuprofen works in the brain and the rest of the body. This means Paracetamol only helps reduce pain and fever, while ibuprofen has the added benefit of reducing inflammation and swelling at the site of an injury.
Paracetamol + ibuprofen is an oral combination of a para-aminophenol analgesic and a non-steroidal anti-inflammatory drug (NSAID) indicated for the temporary relief of minor aches and pains due to headache, backache, muscular aches, toothache, menstrual cramps, or minor pain of arthritis. All NSAIDs, including ibuprofen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and GI perforation of the esophagus, stomach, small intestine, or large intestine and are associated with an increased risk of serious cardiovascular (CV) thromboembolism, including myocardial infarction or stroke. Use the lowest effective dose for the shortest possible duration; the increase in CV risk has been most consistently observed at higher doses.
Paracetamol + Ibuprofen is approved for use in the following clinical indications Mild Pain
Oral dosage (caplets containing 250 mg of Paracetamol and 125 mg of ibuprofen)
Adults:
2 caplets PO every 8 hours while symptoms persist. Do not exceed more than 6 caplets/day.
Children and Adolescents 12 to 17 years:
2 caplets PO every 8 hours while symptoms persist. Do not exceed more than 6 caplets/day
Maximum Dosage Limits:
- Adults
6 caplets/day PO (Paracetamol 1,500 mg/day PO; ibuprofen 750 mg/day PO).
- Geriatric
6 caplets/day PO (Paracetamol 1,500 mg/day PO; ibuprofen 750 mg/day PO).
- Adolescents
6 caplets/day PO (Paracetamol 1,500 mg/day PO; ibuprofen 750 mg/day PO).
- Children
12 years: 6 caplets/day PO (Paracetamol 1,500 mg/day PO; ibuprofen 750 mg/day PO).
1 to 11 years: Safety and efficacy have not been established.
- Infants
Safety and efficacy have not been established.
- Neonates
Safety and efficacy have not been established.
Paracetamol + Ibuprofen is available in various strengths as
Tablet: 500 mg + 200 mg, 325 mg +400 mg, 325 mg + 9.75 mg
Suspension: 100 ml , 60 ml
Paracetamol + Ibuprofen is available in the form of Oral Tablet, Oral suspension
Dosage Adjustment in Kidney Patient
For patients with a CrCl less than 10 mL/minute, administer Paracetamol at a minimum interval of every 8 hours. Chronic use should be discouraged in patients with underlying renal disease.
Avoid use of ibuprofen in patients with advanced renal disease unless the benefits are expected to outweigh the risks of worsening renal function. If use is necessary, monitor renal function closely.
GFR 30 to 60 mL/minute/1.73 m2: Avoid ibuprofen use in patients with intercurrent disease that increases the risk of acute kidney injury.
GFR less than 30 mL/minute/1.73 m2: Avoid ibuprofen use
- Dosage Adjustment in Hepatic impairment Patient
Use Paracetamol with caution in patients with hepatic dysfunction. In patients with chronic hepatic disease, Paracetamol can be used safely; use the smallest dose for the shortest duration necessary. guidelines for dosage adjustments of ibuprofen in hepatic impairment are not available.
- Dosage Adjustment in Pediatric Patient:
Paracetamol : Paracetamol is excreted primarily as the sulfate conjugate in children, due to a deficiency in glucuronide formation in younger pediatric patients. The relative contribution of sulfate and glucuronide conjugation changes with age and normal adult ratios (2:1 glucuronide to sulfate conjugates) are reached by 12 years of age.
Ibuprofen: The elimination half-life of oral ibuprofen in children ranges from 0.9 to
2.3 hours. A higher Vd has also been observed in younger children (younger than 2.5 years) compared with older children. The pharmacokinetics of ibuprofen in adolescents are similar to those seen in adults.
Paracetamol + Ibuprofen is contraindicated in patients with
Hypersensitivity to ibuprofen, paracetamol or other NSAIDs. Active or history of peptic ulceration or haemorrhage (including history of gastrointestinal bleeding related to previous NSAID therapy); severe heart failure (NYHA Class IV), cerebrovascular or other active bleeding, coagulation disorders, history of ulcerative colitis or Crohn’s disease, bronchial asthma, urticaria or allergic- type reactions to aspirin or other NSAIDs, active alcoholism. Treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery, spinal cord injury (IV). Children <18 years of age. Severe hepatic and renal failure. 3rd trimester of pregnancy (oral). Pregnancy and lactation (IV).
Concomitant use with paracetamol- or NSAID-containing drugs (e.g. cyclo- oxygenase-2 inhibitors, aspirin (doses >75 mg daily).
Caution is advised in people with underlying sensitivity to aspirin and other pain killers. Paracetamol + Ibuprofen is contraindicated in children below 12 years of age under 40 kg of weight. If treatment is required for more than three days, consult your doctor. Paracetamol + Ibuprofen should be taken with caution if you have an allergy to paracetamol, ibuprofen, aspirin, or other pain killers, highly sensitive reactions (asthma, lip/face/throat swelling), existing stomach ulcer or bleeding associated pain killers, blood clotting disorder, heart diseases (like congestive heart failure), kidney disease, peptic ulcer, another active bleeding (like brain stroke bleeding), and severe dehydration (due to vomiting, diarrhoea). Liver damage might occur if taken for a longer duration as it contains paracetamol. The skin should be closely monitored as skin allergic reactions like Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported with Paracetamol + Ibuprofen. Blood pressure and cardiovascular (heart) status should be monitored closely during the treatment with Paracetamol + Ibuprofen, especially in people affected with high blood pressure and who have a history of heart failure.
Alcohol Warning
Consumption of alcohol during treatment with Paracetamol + Ibuprofen combination medicine may increase the risk of severe side effects.
Breast Feeding Warning
There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.
Pregnancy Warning
Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
- Common Adverse effects
Depression, insomnia, confusion, emotional lability, and drowsiness
- Less Common Adverse effects
Anxiety, asthenia, malaise, tremor, vertigo, seizures, and coma..
- Rare Adverse effects:
Jaundice, fulminant hepatitis, hepatic necrosis, and hepatic failure
May enhance the effect of anticoagulants (e.g. warfarin).
Paracetamol:
May increase the plasma concentration of chloramphenicol. Increased absorption by domperidone and metoclopramide Decreased absorption by cholestyramine and other drugs that reduce gastric emptying time (e.g. narcotic analgesics, propantheline, antidepressants with anticholinergic properties).
Altered plasma concentration with probenecid. Concomitant use with zidovudine, co- trimoxazole or isoniazid (alone or with other anti-TB drugs) may result in severe hepatotoxicity.
Ibuprofen:
May reduce the effects of ACE inhibitors, angiotensin II antagonists, diuretics and mifepristone. Increased risk of gastrointestinal bleeding with corticosteroids, antiplatelet agents and selective SSRIs.
May increase the plasma levels of cardiac glycosides.
May increase the risk of nephrotoxicity when given with ciclosporin and tacrolimus. May decrease the elimination of lithium and methotrexate. May increase the risk of convulsions associated with quinolone antibiotics. Increased risk of haematological toxicity with zidovudine.
Potentially Fatal: Concomitant use with paracetamol- or NSAID-containing drugs
(e.g. COX-2 inhibitors, aspirin) may result in serious adverse effects.
The common side effects of Paracetamol + Ibuprofen include the following
- Common
Headache, dizziness, lightheadedness, nausea, and flushing.
Rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing, severe tiredness, aching/swollen joints, rash on nose and cheeks, swollen glands, signs of kidney problems (such as change in the amount of urine, bloody/pink urine), signs of infection (such as sore throat that doesn't go away, fever, chills), easy
- Rare
Bruising/bleeding, fainting, fast/irregular/pounding heartbeat.
- Pregnancy
Pregnancy Category C
There are no studies using Paracetamol + Ibuprofen in pregnant women. Isosorbide dinitrate has been shown to cause a dose-related increase in embryo-toxicity (excess mummified
pups) in rabbits at 70 mg/kg (12 times the MRHD of Paracetamol + Ibuprofen on a body surface area basis). Hydralazine hydrochloride is teratogenic in mice at 66 mg/kg and possibly in rabbits at 33 mg/kg (2 and 3 times the MRHD of Paracetamol + Ibuprofen on a body surface area basis). There are no animal studies assessing the teratogenicity of Paracetamol + Ibuprofen. A meta-analysis of randomized controlled trials comparing hydralazine hydrochloride with other antihypertensive agents for severe hypertension in pregnancy found that hydralazine hydrochloride was associated with significantly more maternal hypotension, placental abruption, caesarean sections and oliguria, with more adverse effects on fetal heart rate and with lower Apgar scores. A combination of propranolol and hydralazine hydrochloride was administered to 13 patients with long-standing hypertension during 15 pregnancies. These pregnancies resulted in 14 live births and one unexplained stillbirth. The only neonatal complications were two cases of mild hypoglycemia. Hydralazine hydrochloride and its metabolites have been detected using a non-selective assay in maternal and umbilical plasma in patients treated with the drug during pregnancy. Isosorbide dinitrate has been used for effective acute and sub-chronic control of hypertension in pregnant women, but there are no studies using it in a chronic regimen and assessing its effects on pregnant women and/or the fetus.
● Nursing Mothers
No studies have been performed with Paracetamol + Ibuprofen. It is not known if either hydralazine or isosorbide dinitrate is excreted in human milk.
● Pediatric Use
The safety and effectiveness of Paracetamol + Ibuprofen in children have not been established.
● Geriatric Use
Clinical studies of Paracetamol + Ibuprofen did not include enough subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between elderly and younger patients. In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic and renal function, and of concomitant disease or other drug therapies. Isosorbide dinitrate, its active metabolites, and hydralazine may be eliminated more slowly in elderly patients.
The signs and symptoms of overdosage with Paracetamol + Ibuprofen are expected to be those of excessive pharmacologic effect, i.e., vasodilatation, reduced cardiac output and hypotension, and signs and symptoms include headache, confusion, tachycardia, and generalized skin flushing. Complications can include myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmia, and profound shock. Syncope, coma and death may ensue without appropriate treatment.
- Pharmacodynamic
- Ibuprofen: Ibuprofen competitively inhibits both COX-1 and COX-2 by blocking arachidonate binding resulting in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. The enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step of the synthesis prostaglandins and thromboxanes that are involved in rapid physiological responses. It appears that the anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoenzyme. However, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis. Ibuprofen is slightly more selective for COX-1 than COX-2
● Pharmacokinetics
- Paracetamol :
- Absorption: At therapeutic concentrations, Paracetamol protein binding is about 10% to 25%.
- Distribution: Paracetamol is widely distributed throughout most body tissues except fat; low protein binding and molecular weight allow blood-brain barrier penetration. Vd is approximately 0.7 to 1 L/kg in children and adults. Paracetamol is primarily metabolized in the liver by first-order kinetics and involves 3 separate pathways: glucuronidation, sulfate conjugation, and cytochrome P450 (CYP450) oxidation. Glucuronidation and sulfate conjugation are the major routes of metabolism, while a small amount of drug undergoes oxidative metabolism via CYP2E1 producing the hepatotoxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI).
The Vd of ibuprofen is dependent on patient age and body temperature; febrile children younger than 11 years have a Vd of approximately 0.2 L/kg while adults have a Vd of approximately 0.12 L/kg. Ibuprofen is highly protein-bound (more than 99% at 20 mcg/mL); at serum concentrations more than 20 mcg/mL, protein binding is saturated and becomes nonlinear. Ibuprofen is a racemic mixture. The S-isomer is responsible for clinical activity. The R-isomer is thought to be pharmacologically inactive; however, approximately 60% of the R-ibuprofen is slowly converted to S-ibuprofen in adults. The conversion of R-ibuprofen to S- ibuprofen is lower in children compared with adults.
- Metabolism: At therapeutic doses, NAPQI is rapidly conjugated with glutathione to form inert cysteine and mercapturic acid metabolites. The P450 isoenzymes 1A2 and 3A4 appear to have a minor role in the metabolism of Paracetamol .
Supratherapeutic or repeated therapeutic doses of Paracetamol , fasting, and alcoholism may deplete glutathione stores, leading to increased concentrations of NAPQI and hepatotoxicity.
S-ibuprofen is metabolized via hepatic oxidation by CYP2C9 to inactive metabolites. Plasma half-life of ibuprofen is approximately 2 to 2.5 hours.
- Elimination: The elimination half-life of Paracetamol is 2 to 3 hours in healthy adult patients. Paracetamol is renally excreted primarily as the glucuronide conjugate (40% to 65%) and sulfate metabolite (25% to 35%). Mercapturic acid and cysteine metabolites account for 5% to 12% of the urinary metabolites; less than 5% is excreted as unchanged drug. Ibuprofen is eliminated in the urine and excretion is nearly complete within 24 hours. After ingestion, 45% to 80% of the dose is excreted as metabolites, while approximately 1% and 14% are excreted as free and conjugated ibuprofen, respectively.Some biliary excretion may occur.
- Beneficiary of Paracetamol + Ibuprofen
Paracetamol + Ibuprofen belongs to a class of painkillers called non-steroidal anti-inflammatory drugs (NSAIDs). It relieves symptoms of muscle pain, arthritis pain, dysmenorrhea (painful periods or menstrual cramps), and dental pain and reduces fever.
- Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino Jr R, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. New England Journal of Medicine. 2004 Nov 11;351(20):2049-57.
- Tam SW, Sabolinski ML, Worcel M, Packer M, Cohn JN. Lack of Bioequivalence between Different Formulations of Isosorbide Dinitrate and Hydralazine and the Fixed-Dose Combination of Isosorbide Dinitrate/Hydralazine. Clinical pharmacokinetics. 2007 Oct;46(10):885-95.
- Ferdinand KC. Isosorbide dinitrate and hydralazine hydrochloride: a review of efficacy and safety. Expert Review of Cardiovascular Therapy. 2005 Nov 1;3(6):993- 1001.
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