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Haemophilia A is a bleeding disorder characterized by a deficiency of coagulation factor VIII (FVIII), and the natural approach to haemophilia management is replacement of the missing FVIII. Historically, FVIII replacement therapy required administration of whole fresh blood, fresh or frozen plasma or cryoprecipitate. In the 1970s, freeze-dried concentrates of coagulation factors from human plasma became commercially available, which represented the start of a new era of haemophilia therapy. The availability of factor concentrates dramatically increased access to replacement therapy, made home-based therapy feasible and resulted in improvements in life expectancy and quality of life for patients with haemophilia.1

Development of the solvent/detergent (S/D) viral inactivation method revolutionized the production of FVIII concentrates. This innovative approach, which inactivates lipid-enveloped viruses, was first employed on an industrial scale in the production of plasma-derived biopharmaceuticals by Octapharma in 1986. Subsequently, Octapharma further optimized the manufacture of their FVIII concentrates and included a second virus inactivation step of terminal dry-heat treatment in the production of Octanate®.

Octanate® is a native, human, highly purified plasma-derived (pd) FVIII/von Willebrand factor (VWF) concentrate that combines VWF ristocetin cofactor activity (VWF:RCo) and FVIII activity (FVIII:C) in a ratio of ~0.4. FVIII binding to its natural stabilizer VWF may decrease FVIII immunogenicity due to epitope masking and protection of FVIII from endocytosis by antigen-presenting cells.2,3 Binding of FVIII to VWF also prolongs FVIII half-life by preventing its proteolytic degradation.

Octanate® is derived from plasma from carefully selected donors and collected at highly regulated blood and plasma collection centres. Each individual donation undergoes virus testing for human immunodeficiency virus (HIV), hepatitis A, B and C viruses (HAV, HBV and HCV), and parvovirus B19. Only donations that are free from viruses are released for production. In addition to the extensive viral inactivation steps during its purification, the final Octanate® product meets the European Medicines Agency standards for virus safety.

Over the 20 years since Octanate® was first marketed in Germany in 1998, a wealth of data has been accumulated in clinical studies and in routine clinical practice demonstrating the efficacy and safety of Octanate® in previously treated patients (PTPs) with or without inhibitors, and previously untreated patients (PUPs). Since its development, over 12 billion IU of Octanate® have been infused worldwide. Today, Octanate® is approved in over 80 countries for the treatment and prevention of bleeding, including surgical prophylaxis, in patients with haemophilia A, and in more than 40 countries for immune tolerance induction (ITI).

Clinical development of Octanate®: the clinical trial programme

An extensive phase III programme was undertaken to investigate the efficacy, safety and pharmacokinetics of Octanate® in a variety of clinical settings. Six prospective, open-label, noncontrolled, pivotal studies were conducted in accordance with good clinical practice guidelines. Five of these studies recruited a total of 86 PTPs (children, adolescents and adults) and one study was conducted in 51 PUPs (Table 1). Baseline demographics and clinical characteristics of the pooled PTP population and the PUPs are shown in Table 2.

At the time the pivotal studies were started (late 1990s and early 2000s), severe haemophilia A was defined as FVIII activity (FVIII:C) <2%. The definition of severe haemophilia was later revised to FVIII:C <1%. Even so, 97% of PTPs in the pivotal studies had a basal FVIII:C of ⩽1%. In study AVI-403, 92% of the PUPs had FVIII:C <1%.

Three studies assessed the pharmacokinetic properties of Octanate® as a primary objective; data are summarised in Table 3. The mean half-life of Octanate® after a single administration of an average dose of 40 IU/kg in PTPs ⩾ 12 years of age was between 11.1 and 14.3 h,6 and the mean recovery of Octanate® was in agreement with expected recovery values for FVIII (2.0–2.5% per IU/kg).7 Mean recovery of Octanate® in children under 6 years of age was analysed as a secondary objective in one PTP study and was slightly lower than that in adolescents and adults, as expected due to higher plasma volumes per unit weight in children.

All six studies assessed the efficacy, safety and immunogenicity of Octanate® treatment, either prophylactically or on-demand, with immunogenicity being the primary endpoint in two PTP studies and the PUP study.

Octanate® is effective for the treatment and prevention of bleeding in PTPs

The efficacy of Octanate® in the treatment of bleeding episodes across the five PTP studies was assessed in a pooled analysis, based on the following objective criteria: percentage of bleeds treated successfully (see Figure 1 footnote for criteria), and percentage of bleeds with adequate treatment duration [defined as ⩽2 treatment days for bleeding episodes (⩽7 days for GI bleeding episodes)]. Across the five studies, 76 of the 77 patients experienced 1875 bleeding episodes. The success rate for Octanate® treatment for all bleeding episodes was 92.7% [95% confidence interval (CI): 91.5%, 93.9%] and percentage of bleedings with adequate treatment duration was 94.7% (95% CI: 93.6%, 95.6%). The percentage of bleeding episodes treated for ⩽2 days was 90.8%. When only those bleeding episodes that were treated successfully were taken into consideration, the percentage of bleeds treated in ⩽2 days was 97.9% (Figure 1). The mean (SD) dose per day for successfully treated bleeds was 22.84 (8.96) IU/kg.

In three studies, including a paediatric study, (AVI-402, -406, -408), the efficacy of individual prophylactic infusions of Octanate® was rated by the investigator. A total of 443 prophylactic infusions in 32 patients were rated for efficacy and 100% of these were rated as ‘excellent’.

For long-term prophylaxis against bleeding in patients with severe haemophilia A, doses of 20–40 IU/kg at intervals of 2–3 days are recommended.10 Dosing of Octanate® can also be personalized based on a patient’s pharmacokinetic profile. The Web-Accessible Population Pharmacokinetic Service (WAPPS-Hemo; www.wapps-hemo.org), led by McMaster University, Hamilton, Ontario, Canada,11,12 allows the estimation of pharmacokinetics and the optimization of dosing regimens for individual patients based on only a few sampling time points. Importantly, for patients on Octanate®, an Octanate®-specific population pharmacokinetic model is available in WAPPS.

Octanate® is effective in major and minor surgeries

The efficacy of Octanate® as surgical prophylaxis was assessed in 19 surgical procedures in the 14 adult or adolescent patients in the AVI-401/402 surgery study. The patients were aged 11–38 years, and all but one were receiving FVIII therapy on-demand at study entry. All patients had a basal FVIII:C of <1% and >100 previous exposure days (EDs) to FVIII, except one patient with a basal FVIII:C of 2% and 50 previous EDs. Of the 19 surgical procedures, 6 were classified as major (total hip replacement, arthrodesis of knee, arthroplasty of both knees, total elbow replacement, cholecystectomy and a correction of a talipes equinovarus), 5 as intermediate (1 elongation of Achilles tendon, 2 needle liver biopsies and 2 follow-up procedures for removal of orthopaedic devices), and 8 as minor (7 dental extractions and 1 extraction of an ingrown toenail). Continuous infusion was administered in 6 procedures (5 of the major surgeries and 1 of the follow-up procedures).

Haemostatic effect was assessed as ‘excellent’ or ‘good’ in all 18 evaluated procedures except one (94.4%) due to rebleed at the operation site (elbow replacement). For one procedure (arthrodesis of the knee), an efficacy assessment was not possible due to continued bleeding in the postoperative phase, which was due to an open vessel and was not related to the haemostatic efficacy of Octanate®. The mean (SD) duration of treatment for all procedures was 7.2 (7.1) days (range 1–20 days). Patients received a mean total dose of 18,251.5 IU (range 1000–63,000 IU) of Octanate® and a mean dose of 44.6 IU/kg (range 28.6–68.3 IU/kg) per ED.

One additional surgical procedure was performed in a 2-year-old PTP in the AVI-408 study. The patient underwent a surgical intervention for a thoracotomy and haematoma evacuation. The patient received 7000 IU (approximately 535 IU/kg) Octanate® as bolus injections over 8 EDs, from 3 days prior to the intervention until 4 days after the end of surgery [1000 IU on day 1, 500 IU on days 2 and 3, 2000 IU on day 4 (day of surgery), 1000 IU on days 5 and 6, and 500 IU on days 7 and 8]. Treatment was assessed as effective in terms of haemostasis and was well tolerated. No major bleeding occurred intra- or postoperatively.

In summary, Octanate® provides effective cover during surgery, regardless of surgery type and severity.

Octanate® displays low immunogenicity and excellent efficacy in PUPs

The development of allo-antibodies that neutralize exogenous FVIII, commonly referred to as FVIII inhibitors, remains a major complication of FVIII therapy in the current treatment era. PUPs with severe haemophilia A are at greatest risk of inhibitor development, with approximately 35% developing inhibitors, usually within the first 50 EDs,13–16 whereas an estimated 1% of PTPs develop inhibitors.17 FVIII inhibitor development is thought to be dependent on a number of patient- and treatment-related factors; however, none of these definitively predict inhibitor development, making it difficult to assign risk to individual patients and posing challenges in prevention of inhibitor development.18,19 One recognised risk factor for inhibitors is the type of F8 gene mutation, with mutations that results in the complete absence of functional FVIII (null mutations) conferring the greatest risk for inhibitor development.20–22 Intron-22 and intron-1 inversions and large deletions have been associated with a high risk of inhibitor development, while small insertions and deletions and splice site mutations are usually associated with lower risk.22 Another risk factor, which has been a topic of much debate and research in the last decade, is the type of FVIII concentrate, plasma-derived or recombinant, used in the early treatment of patients. While some studies and meta-analyses reported an increased inhibitor risk with recombinant FVIII (rFVIII) derived from hamster cell lines compared with pdFVIII,16,18,23–27 others found no difference in the risk.13,15,19,28,29

The immunogenicity profile of Octanate® was evaluated in a prospective, open-label, noncontrolled, multinational, multicentre study (AVI-403) in PUPs treated with Octanate®.30 The study included patients who had received no previous treatment with FVIII-containing products and no inhibitor activity [<0.6 Bethesda units (BU)/mL], with ages ranging from 0.01 to 5.6 years. The primary endpoint of the study was the immunogenicity of Octanate® during prophylactic or on-demand treatment over a total of 100 EDs or 5 years, whichever came first. Frequent inhibitor testing was performed at baseline, every 3 or 4 EDs until 20 EDs, and thereafter either every 10th ED or every 3 months, whichever came first. Efficacy in the prevention and treatment of bleeds and in surgical prophylaxis, virus safety and tolerability were examined as secondary endpoints.

A total of 51 PUPs were treated with Octanate®, of whom 80.4% had an identified high-risk/null F8 mutation (including intron 22 inversions, nonsense/stop/splice site mutations and large deletions). At the end of the study, 46 (90.2%) patients had >50 EDs, 2 (3.9%) had 20–49 EDs, and 3 (5.9%) had <20 EDs.

FVIII inhibitors were detected in 5 of 51 (9.8%) patients; 4 (7.8%) had high-titre inhibitors (> 5 BU/mL) and 1 had a low-titre inhibitor (Table 4). Two of the patients with inhibitors had transient inhibitors that disappeared during regular Octanate® treatment without a change in dose or treatment frequency and were not considered clinically relevant. Of note, no FVIII inhibitors developed in PUPs after major surgeries. All patients who developed inhibitors had high-risk/null F8 mutations: either intron 22 inversions (4 patients) or large deletions (1 patient), and all were treated on-demand. No inhibitors developed in patients with non-null F8 mutations or in patients on prophylaxis.

Of the 51 PUPs in the study, 4 had a baseline FVIII:C level ⩾ 1%, and 2 patients who did not develop inhibitors had not had 20 EDs, the time by which most inhibitors occur. Excluding these patients, and thus applying more stringent criteria, the incidence of inhibitors was 11.1% (5/45) for all inhibitors and 8.9% (4/45) for high-titre inhibitors.

Previously reported FVIII inhibitor incidences from five large epidemiological studies in PUPs treated with pdFVIII concentrates ranged from 20% to 33% for all inhibitors, and 12% to 24% for high-responding inhibitors.19 A recent prospective, randomized, controlled trial, SIPPET, showed a cumulative inhibitor incidence of 44.5% in PUPs and minimally treated patients treated with rFVIII, compared with 26.8% in patients treated with pdFVIII/VWF.14 The inhibitor rate observed in the AVI-403 was lower than that observed with pdFVIII/VWF in the SIPPET study, despite there being similar percentages of patients with the null F8 gene mutations in the Octanate® study (80.4%) as in the SIPPET study (86.3% in the pdFVIII/VWF group and 82.1% in the rFVIII group).

In the SIPPET study, no inhibitors developed in 16 PUPs with non-null mutations in the F8 gene following treatment with pdFVIII/VWF concentrates, whereas 27 inhibitors developed in 101 (26.7%) PUPs with null mutations.31 The same pattern was observed in the Octanate® PUP study, in that none of the PUPs who developed inhibitors had a non-null F8 gene mutation.

In addition to the low immunogenicity, Octanate® demonstrated excellent efficacy in PUPs, consistent with its performance in PTP studies. The haemostatic efficacy of Octanate® was overwhelmingly rated as ‘excellent’ (99.7% of 4716 administrations with available efficacy ratings) (Table 5), and the vast majority of bleeds (95.5%) resolved with 1 or 2 days of treatment. Efficacy of all 201 infusions administered for 23 surgical procedures was rated as ‘excellent’.

Octanate® is successful in ITI therapy in patients with inhibitors

If inhibitors develop, patients become resistant to FVIII replacement therapy and haemostasis during bleeding episodes and surgical procedures is difficult to establish. This increases the risk of unmanageable bleeding, thereby putting patients in potentially life-threatening situations, and of associated morbidity, such as severe arthropathy and subsequent disability. ITI is the only proven strategy for FVIII inhibitor eradication. Several ITI protocols are currently in use,32–35 and there is no consensus on the optimal protocol or FVIII concentrate to be used.

Octanate® is one of the FVIII products being evaluated in the ongoing, investigator-initiated, international, open-label, uncontrolled, Observational Immune Tolerance Induction (ObsITI) study. The ObsITI study applies three stringent ITI success criteria to define the efficacy of ITI: inhibitor titre <0.6 BU/mL; FVIII recovery ⩾80% of the predefined reference value of 1.5%/IU per kg body weight within 1 h postinjection; and FVIII half-life ⩾7 h. ‘Complete success’ requires achievement of all three criteria, ‘partial success’ requires achievement of two, and ‘partial response’ requires achievement of one of the three criteria. ITI is considered to have failed if no criteria are met within the 36-month observation period.36

Interim data from the prospective arm of the ObsITI study have been reported for a largely poor prognosis cohort of 48 patients who received ITI with Octanate®, administered mainly according to the Bonn protocol.36 This cohort included both children and adult patients (age range 0.8–28.1 years); 31.3% had failed a previous ITI attempt and underwent rescue ITI in the study. Of the 48 patients, 42 (87.5%) had high-titre inhibitors and 6 (12.5%) had low-titre inhibitors. A total of 40 patients (83.3%) had at least one risk factor historically associated with a poor ITI prognosis.

Following ITI with Octanate®, a persistent negative inhibitor titre was achieved in 38 out of 48 patients (79.2%), FVIII recovery was normalized in 37 patients (77.1%), and half-life was ⩾7 h in 34 patients (70.8%) (Figure 2). The median time to achievement of these success criteria was short, namely 3.94, 5.26 and 10.86 months, respectively. Complete ITI success was achieved in 34 (70.8%) patients; three had partial success (6.3%), and one (2.1%) a partial response. ITI was unsuccessful in 10 patients (20.8%). All six patients with low-titre inhibitors and 28 of 42 (66.7%) of those with high-titre inhibitors achieved complete success. Furthermore, 22 of 35 patients (62.9%) with high-titre inhibitors and ⩾1 poor prognosis factor achieved complete success. Complete success rate was 60% (9/15 patients) in those with prior ITI treatment (rescue ITI) versus 75.8% (25/33 patients) in those without prior ITI (primary ITI).

The study also showed that eradication of inhibitors translated into a clinical benefit: a statistically significant reduction of 86% in mean monthly bleeding rate was observed following elimination of inhibitors. In the 12 months of follow up, none of the 26 patients who achieved complete success and resumed FVIII prophylaxis had a relapse, showing that ITI with Octanate® has a long-lasting tolerizing effect.

The tolerization rate observed in ObsITI is in line with previously published rates for pdFVIII/VWF concentrates in ITI, which range from 64% to 94%.37–42 Much lower success rates of approximately 35% were observed after rFVIII concentrates without VWF became available and were used for ITI,43–46 supporting the favourable effect of VWF in terms of decreasing FVIII immunogenicity. Recently, a complete success rate of 55% was reported in the retrospective Grifols-ITI study analysing ITI success using a pdFVIII/VWF concentrate in a cohort of 60 patients with severe haemophilia and high-titre inhibitors, largely at high risk of ITI failure.46

The time to reach success criteria with Octanate®, particular negative inhibitor titres, was short. In ObsITI, negative inhibitor titre and complete success were achieved with Octanate® in a median of 3.94 months and 10.86 months, respectively.36 In the International ITI study of 115 patients with a good ITI risk profile and mostly treated with rFVIII products (102 patients, 90%), median time to negative inhibitor titre and complete success were 4.6–9.9 months and 10.6–15.5 months (depending on the dose regimen), respectively.47 A retrospective chart review of rFVIIIFc (Eloctate®) reported 4 of 7 primary ITI patients achieved negative inhibitor titres in a median of approximately 6 months and complete success in a median of 8 months.48 The authors speculated that rFVIIIFc may have properties that uniquely promote tolerization but prospective data are needed before definitive conclusions can be drawn.48 Overall, the ObsITI study showed successful management of patients with inhibitors using Octanate®, and based on these data, Octanate® was approved for ITI in haemophilia A patients with inhibitors.

It is important to consider that future ITI protocols might also include nonfactor therapies.49 The recently started investigator-initiated, international, low-interventional MOdern Treatment of Inhibitor-PositiVe PATiEnts with Haemophilia A (MOTIVATE) study will evaluate different approaches in the management of patients with haemophilia A and inhibitors, including the combination of various FVIII concentrates (among them Octanate®) and emicizumab.

Safety profile of Octanate®

The safety profile of Octanate® in the PTP studies was consistent with other pdFVIII products, with Octanate® being well tolerated and few adverse events (AEs) reported. During 2613 EDs in 85 patients across the five PTP studies, there were a total of 35 AEs, of which 9 were classified as serious and 5 as treatment related. The 5 AEs considered treatment related were malaise in one patient; thrombophlebitis at the infusion site in a surgical patient who had been receiving continuous infusion for 8 days; development of antibodies to parvovirus B19 in two children without any clinical symptoms; and development of a low-titre inhibitor in a surgical patient. A causal relationship between the low-titre inhibitor and Octanate® treatment could not be determined, as the patient had frequently received an alternative FVIII product around the time of inhibitor development. Therefore, no cases of confirmed inhibitor development were reported in PTPs.

A total of 21 AEs were considered probably or possibly related to Octanate® in the PUP study: the 5 cases of inhibitor development described above and 16 asymptomatic parvovirus B19 seroconversions. As parvovirus B19 infection is ubiquitous in the general population, it is likely that the 16 children, as well as the 2 PTPs, were exposed through channels other than Octanate® treatment.

In the ObsITI study, Octanate® for ITI was well tolerated, with only one adverse drug reaction reported (dermatitis allergica).

Between August 1998 and November 2017, approximately 9.5 million IU of Octanate® were sold worldwide. Assuming a mean daily dose of 2000 IU, this corresponds to approximately 4.7 million EDs. Inhibitor development (1 report per 677,732 EDs) and hypersensitivity (1 report per 237,206 EDs) were very rare (<1/10,000), and there were no cases of drug-related thromboembolism.

Conclusions

Over the past 20 years, the safety and efficacy of Octanate® in the prevention and treatment of bleeding in patients with severe haemophilia A have been demonstrated consistently in clinical studies. Available data support the use of Octanate® in the treatment of haemophilia A in a variety of populations, including previously treated adults, adolescents and children, as well as PUPs. The low immunogenicity of Octanate® is particularly important for the high-risk previously untreated population. Successful ITI with octanate® was seen in the investigator-initiated ObsITI study, demonstrating the utility of Octanate® in patients who develop inhibitors and have a poor prognosis for ITI success. These clinical trial data are supported by the wealth of clinical experience with Octanate®, which continues to meet the needs of haemophilia A patients for an effective human pdFVIII concentrate with proven low immunogenicity.

Collagen is a protein that is found in many parts of the body, including the cartilage between bones. Since collagen is made up of amino acids, the building blocks of protein, it has been hypothesized that the body can use the amino acids in collagen supplements to protect and rebuild joint cartilage that has been damaged by osteoarthritis (OA) and rheumatoid arthritis (RA). The research on the effectiveness of collagen in these conditions is mixed but shows promise.

What Is Collagen?

Collagen is known as the most abundant protein in the body. It is the main component of the body’s connective tissues and can be found in skin, bones, cartilage, tendons, and teeth. Tough bundles of collagen, called collagen fibers, support most of the body’s tissues and can be found inside and outside cells.

The word "collagen" comes from the Greek word for glue because it acts as a glue between cells and provides structure to the body's organs. For this reason, a drop in collagen levels in the body will cause the skin to lose its shape. Many people therefore take collagen supplements to preserve their skin health. Similarly, low collagen levels can loosen cartilage and tendons, making them more vulnerable to injuries.

Types of Collagen

Natural Collagen

There are 16 types of collagen, with the most common types in the body being:3

• Type I: Found in skin, tendons, internal organs, and the non-mineral parts of the bone
• Type II: Found in cartilage, allowing cartilage to be springy and cushioning the stress on joints
• Type III: Found in the liver, bone marrow, and lymphoid

These three types of collagen make up 80% to 90% of the collagen in the body.

Collagen Supplements

Collagen supplements also come in three types:

• Gelatin
• Hydrolyzed
• Undenatured

Gelatin and hydrolyzed collagen have been broken down from large proteins to smaller bits.3 When collagen is boiled for a long time, it turns into gelatin. Collagen can be further predigested into its basic amino acids and is called collagen hydrolysate, hydrolyzed gelatin, collagen peptides, or hydrolyzed collagen.

Undenatured collagen is not broken down into smaller proteins or amino acids. Undenatured type II collagen (UC-II) is not intended to be used by the body as a collagen rebuilder.

Health Benefits of Collagen for Arthritis

Collagen type II is most often used to treat pain in osteoarthritis and rheumatoid arthritis. It is usually taken from chickens. It is said to work by causing the body to produce substances that fight inflammation, but this has not been proven. Chicken collagen contains the chemicals chondroitin and glucosamine, which may help rebuild cartilage.

However, studies on supplementing with chondroitin and glucosamine have been mixed, and there is no convincing information on the efficacy of these two chemicals on OA.5

Uses in Osteoarthritis

Osteoarthritis (OA), also known as degenerative joint disease, is one of the most common forms of arthritis, affecting more than 32.5 million adults.6 It occurs when the cartilage that protects the joints wears down over time. It is said that collagen supplements may help in rebuilding joints and reduce inflammation in osteoarthritis, but clinical evidence is mixed.

One study showed that when patients with knee osteoarthritis were given acetaminophen and collagen, significant improvements in their joint pain, function, and quality of life were reported.7 This was, however, a small study and included only 39 subjects.

A systematic review focusing on osteoarthritis and cartilage repair found that collagen hydrolysate and undenatured collagen showed some potential as an option for managing osteoarthritis, but further investigation is needed before any definite conclusion on their effectiveness can be made.8

Uses in Rheumatoid Arthritis

Rheumatoid arthritis (RA) happens when the body’s immune system attacks healthy cells by mistake, causing painful swelling mainly in the hand, wrist, and knee joints. In RA, the lining of the joint becomes inflamed, damaging the joint tissue. Research studying the use of collagen supplements in RA has yielded mixed results as well.

A study that looked at both OA and RA noted that reports of positive results with oral collagen in RA remain controversial, particularly when compared with conventional therapies such as methotrexate, a drug designed to slow down the progression of RA.9 Research into oral collagen for OA in the form of UC-II and partially denatured collagen has shown promise as a pain reliever for those suffering from OA.

However, there are still not enough large and long-term studies to verify the effectiveness of collagen in these conditions. Overall, oral collagen supplementation has achieved some positive results against RA in preclinical and clinical studies.

Possible Side Effects

Side effects vary depending on which type of collagen supplement you take, but they are generally minor overall. Possible side effects include:

• Upset stomach
• Diarrhea
• Rashes, or skin reactions
• Nausea
• Constipation
• Heartburn
• Headache

People with allergies to fish, shellfish, chicken, or egg should avoid taking collagen supplements since many of them contain these ingredients.

Collagen supplements haven't been tested for safety, so people who are pregnant or breastfeeding should avoid using these products when possible.

Doses and Preparation

The best dosage for collagen supplements has not yet been established, but studies have used daily doses of between 1 g and 10 g of collagen hydrolysate and 0.1 mg to 1 mg of chicken or bovine type II collagen.10

UC-II should be taken in very small doses, usually 20 mg to 40 mg per day, while gelatin and hydrolyzed collagen should be taken in higher doses, 10 gm per day.3

Collagen supplements come in powder, capsules, drink mixes, concentrated elixirs, gummies, and chewable tablets.

What to Look For

Unlike prescription and over-the-counter medications, the Food and Drug Administration (FDA) does not approve dietary supplements like collagen for safety and ability to produce results. Organizations do exist that oversee nutritional supplements like collagen, however. Look for seals of approval from U.S. Pharmacopeia (USP), ConsumerLab, or NSF International to be sure the products are manufactured properly.3

The USP Dietary Supplement Verification Program gives a USP verified mark to products that met the program's strict testing and evaluation criteria.11

If you are looking for collagen that is easy to take, look for hydrolyzed collagen powder. It usually has no flavor or color, unless it is added, and dissolves easily in beverages, smoothies, soups, and sauces. Powdered collagen can be added to drinks or food. It mixes best with cold liquids but can be added to warm or hot liquids as well, although it will need more mixing if added to hot liquids.

A Word From Verywell

Even though collagen is considered a natural supplement, always tell your healthcare provider if you are taking collagen or any other dietary supplements. Collagen has been shown to be helpful for some people in reducing the symptoms of OA and RA. However, more research is needed for collagen to verify its effectiveness and ensure its safety in different people. That said, collagen supplements usually cause very mild effects. It's still important to watch out for side effects and let your healthcare provider know if you experience any changes to your health while on collagen supplements.

According to the National Organization for Rare Disorders, the severity of hemophilia can also affect symptoms.

In mild cases, a person will most likely experience:

• spontaneous nose bleeds
• bleeding from the mouth or gums
• easy bruising or hematomas
• excessive bleeding following dental or other surgical procedures or injury

Symptoms for people living with the mild form may not show until adulthood.

In moderate cases of hemophilia, a person may experience:

• easy and excessive bruising
• excessive bleeding following surgeries or trauma

Doctors can often diagnose moderate cases by the time the person is 5 or 6. In severe cases of hemophilia, a person may experience spontaneous bleeding, often in the muscles or joints. This can lead to pain and swelling. Without treatment, it can result in arthritis in the affected joints. Doctors can often diagnose severe cases when the person is an infant.
 

Diagnosing hemophilia

Diagnosis of hemophilia involves:

• a review of symptoms
• a clinical evaluation
• a review of personal medical history
• blood tests and other diagnostic testing

If a person has bleeding problems, or if a doctor suspects hemophilia, a physician will ask about the person’s family and personal medical history. A doctor will then perform a physical examination. Blood tests can provide information about how long it takes for the blood to clot, the levels of clotting factors, and which clotting factors, if any, are missing. Blood test results can also help to identify the type of hemophilia and its severity.
 

Treatment for hemophilia

Though no cure exists for hemophilia, doctors can successfully treat the condition. Treatment focuses on replacing the missing protein and preventing complications. It involves giving or replacing the clotting factors that are too low or missing. Scientists can derive clotting factor treatments for replacement therapy from human blood or synthetically produce a form in a laboratory. Synthetically produced factors are called recombinant clotting factors. Doctors often consider recombinant clotting factors as their first treatment choice because they further reduce the risk of transmitting infections that can be present in human blood. However, modern screening techniques have decreased the likelihood of disease transmission from human samples.

There are two main forms of replacement therapy:

• Prophylactic therapy: Some patients will need regular replacement therapy in order to prevent bleeding. This is called prophylactic therapy. Doctors typically recommend regular treatment for people with severe forms of Hemophilia A.
• Demand therapy: This will stop the bleeding on-demand. People living with mild hemophilia may only need demand therapy, which is a treatment that doctors provide only after bleeding begins and remains uncontrollable.

Other treatment options

In 2018, the Food and Drug AdministrationTrusted Source approved a medication called emicizumab-kxwh. This is intended to reduce or prevent the frequency of bleeding episodes in those with hemophilia A, with or without factor VIII inhibitors. A doctor can administer this medication as an injection under the skin. Initially, a person will receive a dose of 3 mg/kg once a week for 4 weeks. After that, they can receive maintenance injections every 1–4 weeks, depending on the dosage. Other hemophilia A treatments include desmopressin, a manufactured hormone that stimulates the release of stored factor VIII, and antifibrinolytic medications, which prevent clots from breaking down. Doctors may prescribe one of several medications for people living with hemophilia B that replace Factor IX, such as Rixubis or Rebinyn.

Treatment complications

Complications from treatment of hemophilia may occur. They can include developing antibodies to treatments and viral infections from human clotting factors. Treatment can also cause blood clots. Getting treatment as soon as possible is important to help reduce the risk of damage to joints, muscles, and other body parts.
 

Living with hemophilia

A person can take several steps to help reduce the risk of excessive bleeding and to protect their joints.

These include:

• regular low impact exercise or non contact sports
• avoiding certain medications, such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and blood thinners, such as heparin
• practicing good dental hygiene

As preventive treatment, a person should follow the doctor’s recommendations regarding when to get injections of clotting factor VIII or IX.

The CDC recommends regular testing for blood-borne infections, such as HIV and hepatitis. They also recommend getting vaccinations for hepatitis A and B. People with hemophilia who receive donated blood products may be at risk of contracting these conditions.

Hemophilia Treatment Centers (HTCs) are available for support. A CDC study of 3,000 people with hemophilia found that those who used an HTC were 40% less likely to die of a complication related to their condition.

To protect against injuries that can cause bleeding, a person can wear protective gear. They should also take extra precautions, such as consulting a physician, when participating in sports or high impact activities.
 

Bleeding after vaccinations

People living with hemophilia may experience bleeding following a shot. However, this should not stop someone from getting vaccinated. Prior to getting a vaccination, a person should consider getting a dose of factor replacement. Following a shot, they should plan to spend about 10 minutes applying pressure to the area. Several factors can affect a person’s safety when getting a shot. A person should speak with a doctor before getting any vaccination to avoid possible complications.

Summary

Hemophilia is an inherited bleeding disorder associated with excessive bruising, nose bleeds, and spontaneous bleeding in severe cases. The condition typically affects males since the mutation occurs on the X chromosome and males have only one copy of it. A person living with hemophilia can take typically manage the condition with factor replacement therapy and lifestyle changes.