Paracetamol + ibuprofen (Bofalgan Plus) Infusion: Optimizing IV Pain Relief with Combined Therapy

Paracetamol + ibuprofen (Bofalgan Plus)

1g+300mg/100mL Infusion

QUALITATIVE AND QUANTITATIVE COMPOSITION

Bofalgan Plus Infusion 1g+300mg/100ml.

Each 100mL vial contains:

Paracetamol.......1000mg

Ibuprofen (as Sodium Dihydrate) ....300mg (Product specs.: Innovator's)

PHARMACEUTICAL FORM

Ø Solution for infusion.

CLINICAL PARTICULARS

Therapeutic indications:

Bofalgan Plus is indicated in adults for the short-term symptomatic treatment of acute moderate pain and the reduction of fever, where an intravenous route of administration is considered clinically necessary and/or when other routes of administration are not possible.

Safety of paracetamol/ibuprofen combinations 

Short-term studies examining the combination of paracetamol and ibuprofen for acute pain relief have not identified any new safety concerns beyond those already known for the individual active substances. However, a 13-week study indicated that the use of this combination may heighten the risk of bleeding compared to the risks associated with each drug alone, suggesting that long-term use should be approached with caution. Additionally, a retrospective cohort study that reviewed health insurance records of over 640,000 patients aged 65 years and older found that the combination of an NSAID and paracetamol was associated with an increased likelihood of hospitalization for gastrointestinal issues, relative to the use of either medication on its own [1].

Although the concurrent use of a proton pump inhibitor appeared to lessen the associated risk, the combination still presented a hospitalization risk that was double that of paracetamol used independently. The hazard ratio for this combination was determined to be 2.55 (95% confidence interval [CI]: 1.98 to 3.28) in comparison to paracetamol alone at a maximum of 3 g/day, and 1.63 (95% CI: 1.44 to 1.85) when compared to NSAIDs alone [1].

 

Consider precautions and side effects of both NSAIDs and paracetamol

 

Paracetamol is typically well tolerated when administered at the recommended dosages; however, there is a risk of unintentional overdose. It is important to advise patients to be mindful of the paracetamol content present in all their medications. In contrast, the use of ibuprofen necessitates additional precautions, particularly for elderly patients. Ibuprofen should be used cautiously and at the lower end of the dosing spectrum in older individuals and those with conditions such as kidney disease, a history of peptic ulcers, asthma, pregnancy, hypertension, or heart failure. It is essential to take into account the patient's other medications, as the concurrent use of diuretics, ACE inhibitors, angiotensin-II receptor blockers, aspirin, or other nephrotoxic agents may heighten the risk of renal impairment associated with NSAIDs.

 

Best Practices for Treating Acute Pain: A Focus on Paracetamol, Ibuprofen, and Rest

Non-pharmacological interventions, such as the application of hot or cold packs and ensuring adequate rest, should be prioritized for the initial management of mild acute pain, followed by the administration of Paracetamol. Experts advocate for a systematic approach to the pharmacological treatment of acute pain. It is advisable to initiate each analgesic at a lower dosage and gradually increase it based on the patient's response and any adverse effects that may arise. Should the pain persist despite reaching the maximum daily dosage of the analgesic, it is essential to reassess the underlying cause before progressing to the next treatment option. Evidence supports the use of Paracetamol and ibuprofen combinations for the short-term management of moderate pain. These combinations may serve as a viable alternative to codeine-based analgesics for patients who do not have contraindications to NSAIDs and for whom Paracetamol alone is inadequate. Additionally, Paracetamol/ibuprofen combinations may be considered as an alternative to higher doses of ibuprofen in certain patients, providing an NSAID-sparing effect. It is important to note that, similar to all NSAID-containing medications, these combinations should not be utilized for extended periods without medical supervision, and patients should be regularly evaluated for efficacy, risk factors, and the ongoing necessity of treatment. Over-the-counter Paracetamol/ibuprofen combinations are not recommended for chronic pain management.

 

Posology and method of administration

Posology:

For intravenous administration and short-term use only for a maximum of two days. Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms.

Adults (weighing > 50kg):

Administer one vial (100mL) of Bofalgan Plus as a 15-minute infusion every 6 hours, as necessary. Do not exceed a total daily dose of four vials (400ml), which equates to 4000mg (4 g) of Paracetamol and 1200 mg of Ibuprofen [2].

Adults (weighing ≤ 50kg):

Adults weighing 50kg or under should be dosed according to their weight, at a dosage of 1.5mL/kg, a 15-minute infusion every 6 hours, as necessary. This equates to a maximum single dose of 75ml (discard remaining medicine in vial), and a total daily dose of 3000mg (3g) Paracetamol and 900mg Ibuprofen [2].

Pediatric population:

Bofalgan Plus is contraindicated in patients under the age of 18 years [2].

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WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK, and GASTROINTESTINAL RISK

Take care when prescribing, preparing, and administering Paracetamol/Ibuprofen IV to avoid dosing errors which could result in accidental overdose and death.

Bofalgan Plus contains Paracetamol, which has been associated with cases of acute liverfailure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with doses of Paracetamol that exceed 4000mg per day and often involve more than one Paracetamol-containing product.

Nonsteroidal anti-inflammatory drugs (NSAIDs), like Ibuprofen, may cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. Bofalgan Plus is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

 

NSAIDS, like Ibuprofen, cause an increased risk of serious gastrointestinal adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or Gl bleeding are at greater risk for serious Gl events.

 

Literature review  

Current research indicates that for certain pain types, the combination of paracetamol and a non-steroidal anti-inflammatory drug (NSAID) may provide superior pain relief compared to the use of either medication alone.

NSAIDs, including ibuprofen, possess analgesic, antipyretic, and anti-inflammatory properties. They function by inhibiting the production of prostaglandins through the blockade of cyclo-oxygenase (COX), which exists in two forms: COX-1 and COX-2. The analgesic and anti-inflammatory benefits are primarily attributed to the inhibition of COX-2.

Although paracetamol is commonly utilized, its precise mechanism of action remains incompletely understood, though it is believed to exert a centrally mediated analgesic effect. Paracetamol exhibits minimal anti-inflammatory properties, suggesting a distinct mechanism of action compared to NSAIDs. The use of two analgesics with differing mechanisms results in an additive effect rather than a synergistic one; the effectiveness of the combination in managing acute pain is approximately equivalent to the total effectiveness of the individual medications.

This effect is mainly pharmacodynamics, as the co-administration of ibuprofen and paracetamol does not significantly influence the pharmacokinetics of either drug.

 

Research has established that the combination of paracetamol and ibuprofen is effective in treating various acute pain conditions, including postoperative pain, dysmenorrhea, and musculoskeletal discomfort. A review conducted by Cochrane examined the effectiveness of a single dose of paracetamol in conjunction with ibuprofen across different dosage combinations after the removal of wisdom teeth. The authors determined that the combination of paracetamol and ibuprofen provides enhanced pain relief compared to the same dosage of either medication used independently, with fewer patients requiring additional analgesics or experiencing side effects. Studies comparing these combinations have indicated that they offer pain relief comparable to that of codeine-based analgesics in acute pain situations, while generally being better tolerated. This suggests that paracetamol/ibuprofen could be considered as an alternative to currently available over-the-counter codeine-containing analgesics for patients who can tolerate non-steroidal anti-inflammatory drugs (NSAIDs).

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Special populations

Elderly: If necessary, the lowest effective dose should be used for the shortest possible duration. Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs. The patient should be monitored regularly for gastrointestinal bleeding during NSAID therapy.

Renal impairment: Caution should be taken with Ibuprofen dosage in patients with renal impairment. The initial dose should be reduced in patients with mild to moderate renal impairment. The dose should be kept as low as possible and be used for the shortest possible duration necessary to control the symptoms. Renal function should be monitored.

 

Hepatic impairment:

The use of Paracetamol at higher than recommended doses can lead to hepatotoxicity and even hepatic failure and death. In patients with additional risk factors for hepatotoxicity, like hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of glutathione in the liver), or dehydration, a total daily dose of 3000mg (3g) Paracetamol should not be exceeded.

 

Method of administration; Bofalgan Plus should be administered as a 15 minute intravenous infusion. In patients weighing less than 50kg for whom a full vial (100mL) is not required, the correct amount should be infused and the remaining solution discarded. Close monitoring is needed notably at the end of the infusion, regardless of administration route particularly for central route infusion, in order to avoid air embolism.

 

Contraindications

This product is contraindicated for use in patients:

• Ø With known hypersensitivity to Paracetamol, Ibuprofen, or other NSAIDs
• Ø With severe heart failure (NYHA Class IV)
• Ø Who have experienced asthma, urticarial, or allergic-type reactions after taking acetylsalicylic acid or other NSAIDs
• Ø With a history of gastrointestinal bleeding or perforation related to previous NSAID therapy or a history of, recurrent peptic ulceration/hemorrhage (two or more distinct episodes of proven ulceration or bleeding) With severe hepatic failure or severe renal failure
• Ø With cerebrovascular or other active bleeding
• Ø With blood clotting disorders and conditions involving an increased tendency to bleed
• Ø With severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake) during the third trimester of pregnancy
• Ø Under the age of 18 years
• Ø Active alcoholism, as chronic excessive alcohol ingestion may predispose patients to hepatotoxicity (due to the Paracetamol component)

 

Special warnings and precautions for use

Ø Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. This medicine is for short-term use and is not recommended for use beyond 2

Ø The use of Paracetamol+ ibuprofen with concomitant NSAIDs, including cyclooxygenase-2 selective inhibitors, should be avoided.

Ø Do not give anything else containing Paracetamol while giving this medicine. In order to avoid the risk of overdose, check that other medicinal products do in Paracetamol or Ibuprofen, observe the maximum recommended doses.

 

Cardiovascular thrombotic events: Use of Ibuprofen, particularly at a high dose (2400mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Patients with uncontrolled hypertension, congestive heart failure (NYHA II-II), established Ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Ibuprofen after careful consideration and high doses (2400mg/day) should be avoided.

Careful consideration should also be exercised before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g., hypertension, hyperlipidemia, diabetes mellitus, and smoking), particularly if high doses of Ibuprofen (2400mg/day) are required.

 

Hepatic impairment: Patients with impaired liver function or a history of liver disease, and who are on long term Ibuprofen therapy or Paracetamol treatment, should have hepatic function monitored at regular intervals, as Ibuprofen has been reported to have a minor and transient effect on liver enzymes. Dose reduction is recommended in patients showing signs of worsening hepatic function. Treatment should be stopped in those patients who develop severe liver failure.

 

Renal impairment: Paracetamol can be used in patients with chronic renal disease without dosage adjustment. There is minimal risk of Paracetamol toxicity in patients with moderate to severe renal failure. However, for the Ibuprofen component of this product, caution should be used when initiating treatment with Ibuprofen in patients with dehydration.

 

NSAIDs have been reported to cause nephrotoxicity in various forms; interstitial nephritis, nephritic syndrome and renal failure. Rena tubular acidosis and hypokalemia may occur following acute overdose and in patients taking ibuprofen products over long periods at high doses (typically greater than 4 weeks), including doses exceeding the recommended daily dose.

The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. The combination of drugs from these three classes should be used with caution, particularly in elderly patients or those with pre-existing renal impairment.

 

Elderly: Caution should be taken about the use of Ibuprofen as it should not be taken by adults over the age of 65 without consideration of co-morbidities and co-medications because of an increased risk of adverse effects, in particular heart failure, gastrointestinal ulceration and renal impairment.

 

Hematological effects: Blood dyscrasias have been rarely reported. Patients on long-term therapy with Ibuprofen should have regular hematological monitoring.

 

Anaphylactoid reactions: Close patient monitoring is recommended, especially at the beginning of the infusion to detect any anaphylactic reaction caused by the active substance or the excipients. At the first signs of a hypersensitivity reaction following the administration therapy must be stopped and symptomatic treatment must be established.

 

Coagulation defects: Products containing Ibuprofen should be used with caution in persons with intrinsic coagulation defects and those on anti-coagulation therapy and should be monitored.

 

Gastrointestinal events: GI bleeding, ulceration, or perforation, which can be fatal, have been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious Gl events, especially in patients having a the history of ulcer complicated hemorrhage, ulcerative colitis, Crohn's disease, patients with porphyria or perforation & in elderly.

 

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid. This product should be discontinued if there is any evidence of gastrointestinal bleeding or ulceration,

 

Hypertension: Caution is advised when prescribing NSAIDs to patients with hypertension Regular pressure should be monitored closely dining Initiation of NSAID treatment and al interval.

 

Heart failure: Fluid retention and edema have been observed in some patients taking NSAIDs, therefore caution is advised in patients with fluid retention or heart failure.

 

Severe skin reactions: NSAIDs may very rarely cause serious cutaneous adverse events such as exfoliative dermatitis, toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), Acute generalized exanthematous pustulosis (AGEP) which can be fatal and occur without warning. It is advisable to avoid use of Paracetamol + Ibuprofen in case of varicella.

 

Pre-existing asthma; Products containing Ibuprofen should not be administered to patients with acetylsalicylic acid-sensitive asthma and should be used with caution in patients with pre-existing asthma.

 

Ophthalmological effects: Patients who develop visual disturbances during treatment with products containing Ibuprofen should have an ophthalmological examination.

 

Aseptic meningitis: For products containing Ibuprofen, aseptic meningitis has been reported only rarely, usually but not always in patients with systemic lupus erythematous (SLE) or other connective tissue disorders.

 

Potential laboratory test interferences: There are certain methods with which the possibility of laboratory interference exists:

 

Urine tests: Paracetamol in therapeutic doses may interfere with the determination of 5-hydroxyindoleacetic acid (5HIAA), causing false-positive results. False determinations may be eliminated by avoiding Paracetamol ingestion several hours before and during the collection of the urine specimen.

 

Masking of symptoms of underlying infections: Paracetamol + Ibuprofen can mask symptoms of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection. This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella.

 

Prolonged use of analgesics: On prolonged use of analgesics, headache may occur which must not be treated by increasing the dose of the medicinal product.

 

Flucloxacillin; Caution is advised if Paracetamol is administered concomitantly with Flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as those using maximum daily doses of Paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

 

Special precautions

Ibuprofen should be used only after strict assessment of the benefit/risk in patients with congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria).

Caution is required in patients with certain conditions, which may be made worse, in patients who react allergically to other substances.

In patients who suffer from hay fever, nasal polyps or chronic obstructive respiratory disorders as an increased risk exists for them of allergic reaction occurring. These may present as asthma attacks (so-called analgesic asthma), Quincke's oedema or urticaria.

 

Interaction with other medicinal products and other forms of interaction

This medicinal product should not be taken with other medicinal products containing Paracetamol, Ibuprofen, acetylsalicylic acid, salicylates or with any other anti-inflammatory drugs (NSAIDs) unless under a doctor's instruction.

Ibuprofen:

As with other Ibuprofen-containing products, the following combinations should be avoided:

NSAIDs may increase the effect of anticoagulants such as warfarin. NSAIDs should not be combined with antiplatelet agents such as ticlopidine due to the additive inhibition of the platelet function..

NSAIDs inhibit the tubular secretion of methotrexate and some metabolic interaction with reduced clearance of methotrexate may also occur as a result. Caution should be exercised If both an NSAID and methotrexate are given within 24 hours, as the plasma levels of methotrexate can increase, resulting in increased toxicity.

Ibuprofen may competitively inhibit the effect of low-dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. The regular, long-term use of Ibuprofen may also reduce the cardioprotective effect of low-dose acetylsalicylic acids.

 References 

[1]. Hay AD, Redmond NM, Costelloe C, Montgomery AA, Fletcher M, Hollinghurst S, Peters TJ. Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial. Health Technol Assess. 2009 May;13(27):iii-iv, ix-x, 1-163. doi: 10.3310/hta13270. PMID: 19454182.

[2]. Axelsson I. Paracetamol plus ibuprofen reduced fever in young children faster than paracetamol alone but not ibuprofen alone. Evid Based Med. 2009 Dec;14(6):174. doi: 10.1136/ebm.14.6.174. PMID: 19949176.