Drugs List

Therapeutic Indications

Uses

HIV infection-combined with other antiretrovirals

Contraindications

Infants weighing less than 3kg
Neonates under 1 month
Breastfeeding
Galactosaemia
Hereditary fructose intolerance
Pregnancy

Precautions and Warnings

Elderly
Family history of hereditary muscular disorders
Predisposition to rhabdomyolysis
Glucose-galactose malabsorption syndrome
Hepatitis
Hepatitis B
Hepatitis C
History of depression
History of myopathy
History of non-traumatic rhabdomyolysis
History of psychiatric disorder
Lactose intolerance
Myopathy
Phenylketonuria
Severe hepatic impairment

Some formulations contain aspartame - caution in phenylketonuria
Treatment does not prevent risk of transmission of HIV
Advise ability to drive/operate machinery may be affected by side effects
HIV therapy: Must be used in combination with other antiretrovirals
Not all available products are licensed for all age groups
Treatment should be initiated by doctor experienced in HIV management
Presentations with sorbitol unsuitable in hereditary fructose intolerance
Some formulations contain fructose
Some formulations contain lactose
Some formulations contain sucrose
Different formulations are not bioequivalent
Autoimmune disorders can occur many months after initiation of treatment
Monitor for signs of osteonecrosis
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Inflammatory symptoms should be evaluated and treated appropriately
Risk of developing opportunistic infections
Discontinue if drug-related rash or other hypersensitivity reactions occur
Discontinue if hepatic function deteriorates in pts with hepatic impairment
Advise patient to avoid aluminium / magnesium hydroxide containing antacids

When combination antiretroviral therapy is initiated in HIV-infected patients with severe immune deficiency, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and can cause serious clinical conditions or aggravation of symptoms. Such reactions are usually observed within the first few weeks or months after treatment initiation. Examples are cytomegalovirus retinitis, mycobacterial infections or Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treated appropriately.

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking raltegravir. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and, organ dysfunction, including hepatic failure. Discontinue immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop. Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping raltegravir treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Patients with pre-existing hepatic dysfunction, including chronic hepatitis, have an increased frequency of hepatic function abnormalities during combination anti-retroviral therapy. These patients should be closely monitored. If there is evidence of worsening hepatic disease in these patients, interruption or discontinuation of therapy should be considered.

Patients with chronic hepatitis B or C who are treated with combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects, and therefore should be closely monitored during treatment.

Pregnancy and Lactation

Pregnancy

Raltegravir is contraindicated during pregnancy.

There are no adequate data on the use of raltegravir during human pregnancy.

Animal studies have shown reproductive toxicity. The potential risk for humans is not known. It is not known if raltegravir crosses the human placenta. The molecular weight (about 483), moderate plasma protein binding and the terminal half-life suggest that exposure of the embryo-foetus will occur. The low lipid solubility might mitigate the amount of exposure.

Briggs (2015) suggests, if indicated, raltegravir should not be withheld because of pregnancy. Briggs (2015) recommends the use of zidovudine during the intrapartum period regardless of current regimen, as this may prevent vertical transmission of HIV to the newborn.

Antiretroviral Pregnancy Registry
A registry has been established to monitor maternal-foetal outcomes in patients inadvertently administered raltegravir while pregnant. Physicians are encouraged to register patients in this registry.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Raltegravir is contraindicated during breastfeeding.

It is recommend that HIV infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV.

It is not known if raltegravir is excreted into human milk.

Studies in rats have demonstrated that raltegravir is excreted in milk. When a maternal dose of 600 mg/kg/day was administered, the mean substrate concentration in milk was approximately 3 times greater than in maternal plasma.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Acne
Alopecia
Anaemia
Anxiety
Arthralgia
Arthritis
Asthenia
Attention disturbances
Autoimmune hepatitis
Bradycardia
Cachexia
Carpal tunnel syndrome
Changes in blood chemistry
Chest discomfort
Chills
Cognitive impairment
Confusion
Creatine phosphokinase increased
Depression
Diabetes mellitus
Disturbances of appetite
Dizziness
Dry skin
Dysgeusia
Dyslipidaemia
Dysphonia
Elevated triglyceride levels
Epistaxis
Erectile dysfunction
Erythema
Facial wasting
Gastro-enteritis
Gastro-intestinal symptoms
Gastrointestinal disorder
Glucosuria
Graves' disease
Gynaecomastia
Haematuria
Headache
Hepatic failure
Hepatobiliary disorders
Herpes infections
Hot flushes
Hypercholesterolaemia
Hyperglycaemia
Hyperhidrosis
Hyperphagia
Hypersensitivity reactions
Hypertension
Hypoaesthesia
Immune Reactivation/Reconstitution Syndrome
Impaired memory
Increase of liver transaminases
Infections
Influenza
Lipodystrophy
Lipohypertrophy
Lymphadenopathy
Menopausal-like symptoms
Molluscum contagiosum
Mood changes
Myopathy
Nasal congestion
Nasopharyngitis
Nephritis
Nephrolithiasis
Neutropenia
Nocturia
Oedema
Osteonecrosis
Osteopenia
Pain
Palpitations
Paraesthesia
Peripheral neuropathy
Polydipsia
Prurigo
Pruritus
Pyrexia
Rash
Reduced platelet count
Renal cysts
Renal impairment
Rhabdomyolysis
Skin papilloma
Sleep disturbances
Somnolence
Stevens-Johnson syndrome
Suicidal tendencies
Tendon inflammation
Tinnitus
Tremor
Upper respiratory tract infection
Urticaria
Ventricular extrasystoles
Vertigo
Visual disturbances
Vomiting
Weight gain

Presentation

Oral preparations containing raltegravir (as potassium).

Drugs List

Therapeutic Indications

Uses

HIV infection-combined with other antiretrovirals

Dosage

Different formulations are not bioequivalent.

Adults

Children

Contraindications

Infants weighing less than 3kg
Neonates under 1 month
Breastfeeding
Galactosaemia
Hereditary fructose intolerance
Pregnancy

Precautions and Warnings

Elderly
Family history of hereditary muscular disorders
Predisposition to rhabdomyolysis
Glucose-galactose malabsorption syndrome
Hepatitis
Hepatitis B
Hepatitis C
History of depression
History of myopathy
History of non-traumatic rhabdomyolysis
History of psychiatric disorder
Lactose intolerance
Myopathy
Phenylketonuria
Severe hepatic impairment

Some formulations contain aspartame - caution in phenylketonuria
Treatment does not prevent risk of transmission of HIV
Advise ability to drive/operate machinery may be affected by side effects
HIV therapy: Must be used in combination with other antiretrovirals
Not all available products are licensed for all age groups
Treatment should be initiated by doctor experienced in HIV management
Presentations with sorbitol unsuitable in hereditary fructose intolerance
Some formulations contain fructose
Some formulations contain lactose
Some formulations contain sucrose
Different formulations are not bioequivalent
Autoimmune disorders can occur many months after initiation of treatment
Monitor for signs of osteonecrosis
Advise patient to seek medical advice if joint aches or pain occur
Advise patient to seek medical advice if movement becomes difficult
Inflammatory symptoms should be evaluated and treated appropriately
Risk of developing opportunistic infections
Discontinue if drug-related rash or other hypersensitivity reactions occur
Discontinue if hepatic function deteriorates in pts with hepatic impairment
Advise patient to avoid aluminium / magnesium hydroxide containing antacids

When combination antiretroviral therapy is initiated in HIV-infected patients with severe immune deficiency, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and can cause serious clinical conditions or aggravation of symptoms. Such reactions are usually observed within the first few weeks or months after treatment initiation. Examples are cytomegalovirus retinitis, mycobacterial infections or Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treated appropriately.

Severe, potentially life-threatening, and fatal skin reactions have been reported in patients taking raltegravir. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and, organ dysfunction, including hepatic failure. Discontinue immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop. Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping raltegravir treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

Patients with pre-existing hepatic dysfunction, including chronic hepatitis, have an increased frequency of hepatic function abnormalities during combination anti-retroviral therapy. These patients should be closely monitored. If there is evidence of worsening hepatic disease in these patients, interruption or discontinuation of therapy should be considered.

Patients with chronic hepatitis B or C who are treated with combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects, and therefore should be closely monitored during treatment.

Pregnancy and Lactation

Pregnancy

Raltegravir is contraindicated during pregnancy.

There are no adequate data on the use of raltegravir during human pregnancy.

Animal studies have shown reproductive toxicity. The potential risk for humans is not known. It is not known if raltegravir crosses the human placenta. The molecular weight (about 483), moderate plasma protein binding and the terminal half-life suggest that exposure of the embryo-foetus will occur. The low lipid solubility might mitigate the amount of exposure.

Briggs (2015) suggests, if indicated, raltegravir should not be withheld because of pregnancy. Briggs (2015) recommends the use of zidovudine during the intrapartum period regardless of current regimen, as this may prevent vertical transmission of HIV to the newborn.

Antiretroviral Pregnancy Registry
A registry has been established to monitor maternal-foetal outcomes in patients inadvertently administered raltegravir while pregnant. Physicians are encouraged to register patients in this registry.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Raltegravir is contraindicated during breastfeeding.

It is recommend that HIV infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV.

It is not known if raltegravir is excreted into human milk.

Studies in rats have demonstrated that raltegravir is excreted in milk. When a maternal dose of 600 mg/kg/day was administered, the mean substrate concentration in milk was approximately 3 times greater than in maternal plasma.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Acne
Alopecia
Anaemia
Anxiety
Arthralgia
Arthritis
Asthenia
Attention disturbances
Autoimmune hepatitis
Bradycardia
Cachexia
Carpal tunnel syndrome
Changes in blood chemistry
Chest discomfort
Chills
Cognitive impairment
Confusion
Creatine phosphokinase increased
Depression
Diabetes mellitus
Disturbances of appetite
Dizziness
Dry skin
Dysgeusia
Dyslipidaemia
Dysphonia
Elevated triglyceride levels
Epistaxis
Erectile dysfunction
Erythema
Facial wasting
Gastro-enteritis
Gastro-intestinal symptoms
Gastrointestinal disorder
Glucosuria
Graves' disease
Gynaecomastia
Haematuria
Headache
Hepatic failure
Hepatobiliary disorders
Herpes infections
Hot flushes
Hypercholesterolaemia
Hyperglycaemia
Hyperhidrosis
Hyperphagia
Hypersensitivity reactions
Hypertension
Hypoaesthesia
Immune Reactivation/Reconstitution Syndrome
Impaired memory
Increase of liver transaminases
Infections
Influenza
Lipodystrophy
Lipohypertrophy
Lymphadenopathy
Menopausal-like symptoms
Molluscum contagiosum
Mood changes
Myopathy
Nasal congestion
Nasopharyngitis
Nephritis
Nephrolithiasis
Neutropenia
Nocturia
Oedema
Osteonecrosis
Osteopenia
Pain
Palpitations
Paraesthesia
Peripheral neuropathy
Polydipsia
Prurigo
Pruritus
Pyrexia
Rash
Reduced platelet count
Renal cysts
Renal impairment
Rhabdomyolysis
Skin papilloma
Sleep disturbances
Somnolence
Stevens-Johnson syndrome
Suicidal tendencies
Tendon inflammation
Tinnitus
Tremor
Upper respiratory tract infection
Urticaria
Ventricular extrasystoles
Vertigo
Visual disturbances
Vomiting
Weight gain

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last full review date: January 2018.

Reference Sources

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Summary of Product Characteristics: Isentress 25mg and 100mg chewable tablets. Merck Sharp and Dohme Limited. Revised October 2018.
Summary of Product Characteristics: Isentress 100mg granules for oral suspension. Merck Sharp and Dohme Limited. Revised October 2018.
Summary of Product Characteristics: Isentress 400mg film-coated tablets. Merck Sharp and Dohme Limited. Revised October 2018.
Summary of Product Characteristics: Isentress 600mg film-coated tablets. Merck Sharp and Dohme Limited. Revised October 2018.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 16 January 2018

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Raltegravir. Last revised: 10 March 2015
Last accessed: 16 January 2018.